Acute myeloid leukemia is a heterogeneous blood cancer in which genetic alterations, including mutations in DNMT3A, TET2, ASXL1 and IDH1 or IDH2, interact with dynamic changes in DNA methylation, histone marks, higher-order chromatin organization and gene expression. This combination sustains the capacity of malignant cells to self-renew, resist differentiation and move between transcriptional states. Because many epigenetic changes are reversible, they offer attractive therapeutic targets. Yet the same plasticity can let residual cells adapt, allowing pre-leukemic clones to survive and disease to relapse. The review therefore treats AML not as a collection of isolated molecular defects, but as a system in which relatively stable mutations establish a permissive framework that is continually reshaped by epigenetic regulation.

Hypomethylating agents such as azacitidine and decitabine were the first epigenetic drugs incorporated into routine myeloid treatment. They trap the DNA methyltransferase DNMT1 and promote passive loss of methylation during cell division, partially restoring silenced genes associated with differentiation and tumor suppression. Their principal role is disease modification rather than rapid elimination of leukemic blasts. The addition of venetoclax substantially improved remission and survival in the phase III VIALE-A trial for newly diagnosed patients unsuitable for intensive chemotherapy, but median survival was still measured in months rather than years, and outcomes varied with mutations such as NPM1, IDH1/2 and TP53. Failure is often linked to incomplete demethylation, compensatory methylation regulators, persistent founder clones and resilient leukemic stem-cell compartments, even when bulk blast measurements suggest a response.

Mutant IDH1 and IDH2 offer a more genetically defined route into the same methylation machinery. These enzymes produce the oncometabolite R-2-hydroxyglutarate, which inhibits TET enzymes and JmjC-domain histone demethylases, producing widespread hypermethylation and impaired myeloid differentiation. Ivosidenib and enasidenib demonstrated that suppressing this metabolite can restore differentiation, although responses are often incomplete and relapse remains common. The phase III AGILE trial subsequently showed that ivosidenib plus azacitidine improved event-free and overall survival over azacitidine alone in newly diagnosed, intensive-therapy-ineligible IDH1-mutant AML. Resistance nevertheless emerges through inhibitor-binding mutations, switching to the other IDH isoform, activation of proliferative signaling, altered metabolism and expansion of pre-leukemic or IDH-wild-type clones. Correcting metabolism can therefore create a differentiation window without removing every survival route.

Menin inhibitors attack a different regulatory layer by disrupting the KMT2A-menin complex, which sustains HOXA9 and MEIS1 programs in KMT2A-rearranged and NPM1-mutated disease. Revumenib, an oral menin inhibitor, produced complete remission or complete remission with partial hematologic recovery in roughly one fifth of evaluable patients in the phase I/II AUGMENT-101 trials, with some responders proceeding to allogeneic transplantation. It also illustrates the gap between molecular correction and clinical control. MEN1 mutations can impair revumenib binding, while TP53 inactivation may blunt apoptosis even when HOX and MEIS targets are successfully downregulated. Other work indicates that loss of PRC1.1 components can reactivate noncanonical targets such as MYC. Combination regimens are consequently being evaluated with hypomethylating agents, venetoclax, intensive chemotherapy and other targeted drugs, but longer follow-up is needed to establish durable benefit.

Several other chromatin targets remain investigational rather than established treatments. The DOT1L inhibitor pinometostat strongly suppressed H3K79 methylation yet produced few objective responses, apparently because some resistant cells continued to rely on DOT1L as a physical scaffold within the KMT2A complex rather than on its catalytic activity. Broad histone deacetylase inhibition has similarly been limited by a narrow therapeutic window and toxicity, encouraging interest in selective agents such as HDAC6 inhibitors. LSD1 inhibitors can promote myeloid maturation in models, but early clinical data remain limited and adaptive chromatin co-dependencies may undermine monotherapy. BET inhibitors have produced occasional responses while causing myelosuppression and other toxicities; preclinical studies show that rapid redistribution of the P300 acetyltransferase can preserve oncogenic transcription after BET blockade. Newer targets include PRMT5 in spliceosome-mutant disease and KAT6A/KAT7 in NUP98-rearranged leukemia, for which early clinical or preclinical evidence supports further biomarker-guided combination studies.

Non-coding RNAs provide another, still exploratory layer within these networks. Most act after transcription by promoting messenger RNA degradation, repressing translation or acting as molecular sponges, but selected long non-coding RNAs have been proposed to interact directly with chromatin regulators. HOTTIP is elevated in KMT2A-rearranged and NPM1-mutated models and has been reported to interact with WDR5/KMT2A complexes, helping maintain active chromatin at the HOXA locus. Disrupting HOTTIP in preclinical models reduced HOXA transcription, impaired clonogenic growth and prolonged survival. HOXA-AS2 has separately been proposed to recruit EZH2 and PRC2 to targets including LATS2, reinforcing repressive H3K27me3 chromatin. These observations remain context-dependent, and the specificity of many lncRNA-chromatin interactions is disputed. The review therefore does not classify non-coding RNAs as a separate epigenetic axis comparable to DNA methylation or histone modification.

Clinical translation of non-coding RNA biology is constrained by variable expression, functional redundancy among RNA family members, inconsistent results across cohorts and differences in samples, platforms and normalization methods. Delivering oligonucleotides or small interfering RNAs directly into leukemia cells also presents obstacles involving delivery, toxicity and compensation by parallel regulatory circuits. Their nearer-term value may therefore lie in measurement rather than direct treatment. HOXA-associated RNAs such as HOTTIP and HOXBLINC could potentially indicate how completely menin inhibition has silenced HOX loci, while other non-coding RNAs may help classify residual disease or track differentiation. These remain hypotheses requiring prospective testing alongside genomic, methylation and chromatin readouts, not established clinical markers.

The review’s central conclusion is that resistance in AML extends beyond ordinary drug failure or secondary mutations. Leukemic cells can preserve core survival programs by changing cofactors, reactivating alternative transcriptional circuits and maintaining epigenetic states in stem or progenitor compartments. This explains why strong laboratory activity has rarely translated into durable benefit in unselected patients, and why indiscriminate combinations have sometimes added toxicity without improving survival. Near-term progress is more likely through trials selected by molecular dependencies, combinations that address cooperating pathways, schedules designed around predictable adaptation, and single-cell multi-omics that distinguish temporary blast reduction from genuine reprogramming. Epigenetic therapy remains clinically actionable in AML, but its future depends on treating the network and measuring the state of its cells, rather than assuming that correcting one regulator is enough.

Subject of Research: Network redundancy, resistance mechanisms and non-coding RNA modulation in epigenetic therapy for acute myeloid leukemia

Article Title: Epigenetic therapy in AML: network redundancy, resistance, and non-coding RNAs

Article References: Fernandes, M. D. C. R., Scandolara, T. B., Mota, J. A., Manso, M. P., Furtado, G. P., Maranhão, S. S., Pessoa, C. D. Ó., & Furtado, C. L. M. (2026). Epigenetic therapy in AML: network redundancy, resistance, and non-coding RNAs. Epigenetics Communications, 6(1), Article 14. https://doi.org/10.1186/s43682-026-00054-6

Image Credits: AI Generated

DOI: 10.1186/s43682-026-00054-6

Keywords: acute myeloid leukemia, epigenetic therapy, DNA methylation, chromatin regulation, menin inhibitors, IDH inhibitors, hypomethylating agents, non-coding RNAs, drug resistance, cancer genomics, Epigenetic, therapy

Diabetic retinopathy is a progressive microvascular complication whose prognosis and management change substantially as it advances from non-proliferative disease to pathological neovascularization in proliferative diabetic retinopathy. Fundus photography and optical coherence tomography effectively identify established structural abnormalities, but they offer limited information about early molecular changes or the likelihood of an imminent stage transition. Existing blood markers, including vascular endothelial growth factor, inflammatory mediators, oxidative-stress indicators and metabolic measures, often reflect systemic disease, vary substantially among individuals and do not reliably distinguish retinal stages. The authors therefore propose a framework in which molecular testing would complement, rather than replace, established imaging.

MicroRNAs are short ncRNAs, generally about 18–25 nucleotides long, that regulate messenger RNA stability and translation. Long non-coding RNAs, usually longer than 200 nucleotides, influence chromatin, transcription and post-transcriptional regulation, while circular RNAs have covalently closed structures that make them comparatively resistant to degradation. All three classes have been linked in experimental and clinical literature to endothelial dysfunction, inflammation, oxidative stress and angiogenesis, processes that are central to diabetic retinopathy. MicroRNAs are the most extensively investigated circulating class and currently provide the most reproducible stage-associated signals, although evidence for most individual candidates remains limited by small cohorts, cross-sectional designs and inconsistent methods.

Early-stage evidence is particularly sparse and requires careful qualification. MicroRNA-3976 was reported as increased in a serum extracellular-vesicle fraction in a discovery and internal validation study comparing 18 people with early NPDR and diabetes but no retinopathy. MicroRNA-23a-3p was lower in serum in a single cohort of 45 people, while microRNA-126-5p was lower in plasma in an RNA-sequencing discovery, quantitative reverse-transcription PCR validation and clinical cohort involving mild NPDR. MicroRNA-26a-5p was associated with retinal nerve fibre layer thinning in an early-disease correlation study. These candidates are “anchored” to explicit early-stage comparisons or retinal structural changes, but the review’s qualitative grading assigned them low evidence because of limited replication and validation.

More established signals appear at more advanced stages. MicroRNA-21, which rises across the non-proliferative-to-proliferative severity continuum, has produced some of the strongest reported discrimination results. One study reported an area under the receiver operating characteristic curve of 0.89, with 95% confidence interval 0.86–0.96, sensitivity of 82–86% and specificity of 84–95% for distinguishing PDR from NPDR, and the review rated its evidence as moderate because it involved three independent cohorts and multistage validation. A three-microRNA serum panel comprising microRNA-21, microRNA-181c and microRNA-1179 also achieved an AUC of 0.89 for PDR versus NPDR across two validation sets. These are cross-sectional diagnostic results, not evidence that baseline microRNA levels predict subsequent progression.

Severe NPDR is the pivotal clinical transition because it precedes overt neovascularization and is associated with substantial near-term risk. Natural-history evidence cited in the review indicates approximately a 50% one-year risk of PDR conversion for severe NPDR and more than 75% for very severe NPDR. MicroRNA-21 reportedly increases progressively from normal fundus through advancing NPDR to PDR, whereas microRNA-34a declines, a pattern the authors interpret as complementary evidence of increasing inflammatory and angiogenic signaling alongside depletion of cytoprotective reserves. Yet these gradients are largely derived from cross-sectional studies. Direct comparisons of mild versus moderate NPDR, moderate versus severe NPDR, and severe NPDR versus early PDR are uncommon, and few studies preselected these adjacent-stage contrasts as primary endpoints.

Long non-coding RNAs and circular RNAs occupy a different evidentiary position. The EV-associated PPT2-EGFL8 transcript was lower in PDR than in non-PDR and diabetes-without-retinopathy groups, while NR2F1-AS1 increased across healthy, diabetes, NPDR and PDR categories. MIAT, HOTTIP and SNHG16 were higher in PDR than NPDR, and the circular RNA hsa_circ_0001953 was elevated in PDR compared with NPDR and healthy controls. Serum EV-associated circMKLN1 also rose across control, diabetes, NPDR and PDR groups. Each finding came from a single small, cross-sectional study, however, with no longitudinal prediction or independent replication. The review accordingly treats these molecules as advanced-stage-associated or context-defining candidates rather than standalone diagnostic markers.

Extracellular vesicles may help stabilize circulating ncRNAs because their lipid membranes protect cargo from enzymatic degradation, and they can selectively package molecules involved in intercellular communication. This has led some researchers to describe vesicle-associated ncRNAs as potentially enriched for disease-relevant signals. The review warns, however, that vesicle association does not establish retinal origin. Blood–retinal barrier disruption is more pronounced in advanced disease and may partly explain why circulating signals are easier to detect in PDR. Isolation methods such as ultracentrifugation, polymer precipitation and size-exclusion chromatography also differ in yield, purity and enrichment, while particle size or a common marker alone cannot prove that a preparation consists of endosome-derived exosomes. Serum, plasma, total circulating RNA and EV-enriched fractions therefore cannot be treated as interchangeable.

The proposed solution is a hierarchy of purpose-built panels rather than a longer catalogue of isolated markers. MicroRNAs would provide core effector readouts, while lncRNAs and circRNAs could add regulatory context and vesicle compartments could improve analytical stability. A competing-endogenous-RNA framework offers a biological rationale for combining them: lncRNAs and circRNAs can buffer shared microRNAs, meaning that a transcript’s diagnostic behavior may depend on its network and disease context rather than its abundance alone. Such interactions are often inferred from correlations or computational predictions, so direct binding, perturbation and rescue evidence are needed before a predicted relationship can be treated as established molecular competition.

Clinical translation would depend on cohorts designed around the difficult transitions rather than broad DR-versus-no-DR comparisons. The review calls for longitudinal, severity-stratified and imaging-integrated studies with prespecified endpoints, independent multicenter validation, adjustment for age, renal function, glycemic control, systemic inflammation, diabetes duration, medication use and relevant comorbidities, and transparent controls for hemolysis, vesicle characterization and RNA normalization. Machine learning and multi-omics may help refine biologically grounded panels, but they cannot replace mechanistic or prospective validation. Until adjacent-stage discrimination and incremental value beyond imaging are demonstrated, circulating ncRNA panels remain promising but unproven decision-support tools rather than clinically established tests for diabetic retinopathy.

Subject of Research: Stage-specific circulating and extracellular vesicle-associated non-coding RNAs as potential biomarkers for diabetic retinopathy

Article Title: Circulating and extracellular vesicle-associated non-coding RNAs in diabetic retinopathy: a stage-aware framework for network-informed biomarker panels

Article References: Yu, J.-W., Choi, M.-J., Lee, D. C., & Park, J.-H. (2026). Circulating and extracellular vesicle-associated non-coding RNAs in diabetic retinopathy: a stage-aware framework for network-informed biomarker panels. Frontiers in Endocrinology, 17, Article 1970838. https://doi.org/10.3389/fendo.2026.1970838

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1970838

Keywords: diabetic retinopathy, non-coding RNAs, microRNAs, long non-coding RNAs, circular RNAs, extracellular vesicles, biomarker panels, risk stratification, liquid biopsy, Circulating, extracellular, vesicle-associated

Macrophages are immune cells that can adopt different functional states within the tumor microenvironment. The review describes a balance between pro-inflammatory M1 macrophages and pro-tumorigenic M2 macrophages. M2 polarization can favor processes associated with tumor progression, whereas M1 polarization is linked in the reviewed evidence to inhibition of tumor growth.

Several non-coding RNAs are linked with M2 polarization in the review. miR-934, lncRNA RPPH1 and circPLCE1 are associated with M2 polarization and metastasis through signaling involving PI3K/AKT, NF-κB and STAT3. Their effects are presented as part of the molecular communication networks that connect colorectal cancer cells with tumor-associated macrophages. The review places these molecules within the broader biological context of tumor progression and metastatic behavior.

Other non-coding RNAs are associated with the M1 state. miR-195-5p and lncRNA GAS5 are described in the reviewed literature as favoring M1 polarization and suppressing tumor growth. The contrast between these molecules illustrates that non-coding RNA activity can be associated with different macrophage states and opposing effects on tumor-related processes. The mechanisms summarized in the review include exosomal transfer, competing endogenous RNA interactions and transcriptional regulation.

Transcriptional regulation provides another level at which these signals can affect cellular behavior. Together, these mechanisms form intricate communication networks between colorectal cancer cells and immune components, including tumor-associated macrophages. The review also discusses the possible translational applications of this biology.

Circulating exosomal non-coding RNAs are presented as candidate biomarkers that could improve diagnostic precision, and ncRNA-regulated macrophage polarization is identified as a possible target for immunomodulatory and precision-treatment strategies. These are research opportunities rather than established clinical benefits. Colorectal cancer remains a major global health burden, with incidence and mortality rates continuing to rise worldwide, according to the review.

The article cites a projection of 3.2 million colorectal cancer cases by 2040 and attributes this expected burden to complex interactions among genetic, environmental and lifestyle factors. The review positions ncRNA signaling within this wider disease context because these molecules may influence tumor-cell behavior, immune evasion, therapeutic resistance and the states of macrophages in the tumor microenvironment. Its central conclusion is that targeting ncRNA-regulated macrophage polarization holds promise for developing next-generation precision therapies and advancing immunomodulatory strategies in colorectal cancer.

That conclusion is a direction for research, not evidence of clinical efficacy. The review’s contribution is to assemble current knowledge about how microRNAs, long non-coding RNAs and circular RNAs relate to macrophage polarization and cancer progression, providing a framework for further investigation of these molecular connections.

Subject of Research: Non-coding RNA regulation of tumor-associated macrophage polarization in colorectal cancer

Article Title: Macrophage polarization and non-coding RNAs in colorectal cancer progression and metastasis

Article References: Nami, M. T., Fattahiyan, I., Eini, P., Eramian, M., & Vanan, A. G. (2026). Macrophage polarization and non-coding RNAs in colorectal cancer progression and metastasis. Medical Oncology, 43(11), Article 350. https://doi.org/10.1007/s12032-026-03482-5

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03482-5

Keywords: colorectal cancer, non-coding RNAs, tumor-associated macrophages, macrophage polarization, microRNAs, long non-coding RNAs, circular RNAs, cancer metastasis, tumor microenvironment, exosomal biomarkers, Macrophage, polarization

The included studies were assessed as direct when a prior stressor induced a macrophage or monocyte molecular or functional state that persisted after removal of the initiating stimulus, was maintained over time or through cell division, or altered the response to a subsequent challenge. Mechanistic studies demonstrated a relevant macrophage or monocyte mechanism without directly establishing persistence or recall, while contextual studies provided broader support. The review used this evidence base to develop the Macrophage Environmental Memory Systems, or MEMS, Framework.

It organizes the literature into six non-mutually-exclusive modules: transposable element regulation, represented in 107 studies; metabolic and signaling reprogramming, in 86; epigenetic regulation, in 33; systems integration, in 17; non-coding RNA regulation, in 14; and extracellular-vesicle-mediated communication, in seven. The overlapping assignments show that the proposed mechanisms are not confined to isolated molecular layers. Transposable element regulation was the most frequently represented module, appearing in 107 of the included studies.

Metabolic and signaling reprogramming was also prominent, with 86 studies assigned to it. Epigenetic regulation appeared in 33 studies, while systems integration, non-coding RNA regulation and extracellular-vesicle-mediated communication appeared in 17, 14 and seven studies, respectively. Together, these counts map the breadth of the literature that may be relevant to acquiring, maintaining, integrating or communicating persistent macrophage states.

The authors present MEMS as an evidence-organizing and hypothesis-generating framework rather than a validated six-component biological pathway. Its purpose is to bring together research that has developed across trained immunity, epigenetic regulation, non-coding RNAs, transposable elements, extracellular vesicles and immunometabolism. The framework does not establish that every module contributes causally to environmental memory, nor does it demonstrate that all six operate together as a single process.

The review also introduces the Macrophage-Mediated Molecular Memory, or M3, hypothesis. This is described as a downstream, experimentally testable extension of MEMS involving the possible communication of environmentally acquired molecular information. It is distinct from the evidence establishing the MEMS Framework itself and remains a hypothesis rather than a demonstrated mechanism.

Future work must determine which mechanisms causally establish and maintain persistent macrophage states. The authors specifically call for exposure-withdrawal studies, longitudinal observations, lineage tracing, perturbational experiments and rechallenge studies. These designs would address the central evidential problem identified by the review: showing not only that macrophages respond to environmental conditions, but that a state persists after the initiating stimulus is removed or that the cells respond differently to a subsequent challenge.

Overall, the systematic review supports the existence of numerous candidate molecular processes that may be relevant to macrophage environmental memory, while finding comparatively little direct evidence of persistence or altered subsequent responses. The MEMS Framework consolidates a scattered literature into six interacting areas for further testing, but the review’s restrictive conclusion is equally important: the biological plausibility of candidate mechanisms has not yet been matched by broad, direct demonstration that macrophages retain an environmental memory.

Subject of Research: Systematic review of molecular evidence for persistent environmental memory in macrophages and monocytes

Article Title: Environmental memory in macrophages: a PRISMA-guided systematic review and the macrophage environmental memory systems framework

Article References: Ruden, D. M. (2026). Environmental memory in macrophages: a PRISMA-guided systematic review and the macrophage environmental memory systems framework. Frontiers in Systems Biology, 6, 1955135. https://doi.org/10.3389/fsysb.2026.1955135

Image Credits: AI Generated

DOI: 10.3389/fsysb.2026.1955135

Keywords: macrophages, environmental memory, monocytes, systematic review, trained immunity, epigenetic regulation, transposable elements, immunometabolism, non-coding RNAs, extracellular vesicles, Environmental, memory

PI3K/AKT signaling is frequently and persistently activated in HCC, an aggressive malignancy of the digestive system that is often diagnosed at an intermediate or advanced stage. The pathway regulates cell survival, growth, proliferation, apoptosis and metabolic homeostasis, and its principal components include PI3K, AKT, PTEN and numerous upstream and downstream regulators. When extracellular growth factors bind receptor tyrosine kinases, class I PI3K converts phosphatidylinositol 4,5-bisphosphate into phosphatidylinositol 3,4,5-trisphosphate, or PIP3. PIP3 recruits AKT and PDK1 to the cell membrane, where AKT is activated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2. PTEN normally restrains the signal by dephosphorylating PIP3, while persistent pathway activation can support tumor-cell proliferation, invasion and metastasis through downstream effectors.

The review separates canonical epigenetic regulation from RNA-mediated control. Epigenetic mechanisms alter gene activity without changing the underlying DNA sequence and include DNA methylation, histone modifications and ATP-dependent chromatin remodeling. DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B, establish or maintain methylation patterns, whereas TET enzymes support active demethylation. Histone acetylation, methylation, phosphorylation, ubiquitination and lactylation are controlled by opposing enzyme systems. Non-coding RNAs provide another regulatory layer: microRNAs, long non-coding RNAs and circular RNAs can influence messenger-RNA stability, translation, alternative splicing, protein ubiquitination and protein degradation. Long non-coding RNAs may also recruit chromatin-modifying complexes. These processes occur within a disease environment shaped by chronic injury, inflammation, fibrosis, cirrhosis, metabolic dysregulation, hypoxia and immune-stromal remodeling.

DNA methylation provides several experimental routes to sustained PI3K/AKT activation. ZNF191 can bind the DNMT1 promoter and increase DNMT1 expression in HCC models, altering genome-wide methylation and activating the pathway. Six2-driven DNMT1 activity hypermethylates the E-cadherin promoter, reducing E-cadherin expression while promoting epithelial-to-mesenchymal transition, PI3K/AKT/mTOR activation and resistance to 5-fluorouracil. TERT and Sp1 can cooperate to increase DNMT3B, producing promoter hypermethylation and silencing of PTEN and RASSF1A. Other methylation events silence NNAT or PDE7B, whose loss weakens restraint on pathway kinases. In the opposite direction, hypomethylation of the FBXO32 promoter increases FBXO32, which promotes ubiquitin–proteasome degradation of the AKT inhibitor PHLPP2. TET1-mediated demethylation has also been associated with PI3K/AKT/mTOR activation, increased proliferation and reduced apoptosis in HCC cell models.

Non-coding RNAs can sustain the pathway by altering RNA metabolism or the stability of signaling proteins. The oncogenic lncRNA IGFRIL recruits PTBP1, accelerating degradation of IGFBP3 messenger RNA and increasing activity of the IGF1R/AKT/mTOR axis. SP1-induced USP27X-AS1 recruits the deubiquitinase USP7, reducing AKT ubiquitination and degradation and thereby increasing AKT stability. Hypoxia can activate additional feedback loops. HIF-1α induces KDM4A-AS1, which sequesters miR-411-5p, increases KPNA2 expression and promotes AKT signaling; elevated KPNA2 and AKT activity can in turn increase HIF-1α. A parallel loop involving MAPKAPK5-AS1, miR-154-5p and PLAGL2 links hypoxia to EGFR/PI3K/AKT activation. Other examples include RP11-295G20.2 binding PTEN and promoting its lysosomal degradation, and circMRPS35 sequestering miR-148a so that increased STX3 drives PTEN degradation.

Histone modifications provide further links between chromatin state and pathway activity. Reduced PCK1 expression lowers S-adenosylmethionine synthesis and the repressive H3K9me3 mark at the S100A11 promoter, derepressing S100A11, which binds and activates AKT1. Overexpressed EZH2 deposits H3K27me3 at the miR-622 promoter, silences that microRNA and releases the CXCR4 axis, leading to PI3K/AKT and RAF/MEK/ERK activation. In HCC cells, MBD3 recruits the NuRD complex to deacetylate the TFPI2 promoter and silence a gene that normally restrains PI3K/AKT signaling. Metabolic reprogramming adds another connection: PYCR1-driven glycolysis raises intracellular lactate, promotes H3K18 lactylation at the IRS1 promoter and increases IRS1 expression. Lactate-associated H3K14 lactylation can increase NEDD4, which promotes PTEN degradation and has been linked to chemoresistance in experimental models.

Evidence that activated PI3K/AKT remodels the epigenome is comparatively limited. One reported mechanism involves AKT increasing DNMT3B transcription while raising HuR expression, extending DNMT3B messenger-RNA half-life and increasing its translation. The resulting rise in DNMT3B disrupts genome-wide methylation in HCC models. AKT can also phosphorylate the acetyltransferase p300 at Ser1834, increasing its activity and H3K9 acetylation at the HMGA2 promoter. Related experimental work links AKT-mediated p300 activity to H3K9 acetylation at the DKK1 locus, while MEK/ERK-dependent PKM2 activity contributes to H3T11 phosphorylation at the same locus. These histone changes increase DKK1 expression and the invasive or metastatic potential of the cells. Another study reports that EGF-associated PI3K/AKT activation raises HDAC2 expression, which increases cell-cycle proteins, accelerates the G2/M transition and promotes proliferation.

Clinical experience with targeted agents that might interrupt this network remains limited. In a small advanced-HCC cohort within a phase II basket trial, the pan-class I PI3K inhibitor buparlisib had poor tolerability, including elevated transaminases, anxiety and depression. Dual PI3K/mTOR inhibitor dactolisib produced severe diarrhea and liver-function abnormalities in solid-tumor studies without dedicated advanced-HCC cohorts, and development was suspended after limited antitumor activity and poor long-term tolerability. Samotolisib produced transient disease control in a subset of patients, but hyperglycemia and elevated transaminases limited prolonged treatment. AKT inhibitors have reached early-phase solid-tumor testing, but no phase II HCC data were available for MK-2206, and capivasertib had not entered a dedicated HCC trial. These findings establish clinical evaluation of the drug classes, not proof of efficacy in HCC.

Epigenetic agents face their own constraints. Decitabine and azacitidine inhibit DNA methyltransferases, but dose-limiting myelosuppression and possible liver injury complicate their use, particularly in patients with hepatic dysfunction. In a phase I study of vorinostat plus sorafenib, thrombocytopenia and liver injury were frequent dose-limiting toxicities, and no recommended phase II dose was established. Resminostat plus sorafenib was evaluated in the phase I/II SHELTER trial, where mild gastrointestinal adverse events predominated; cross-trial comparisons suggest better tolerability for the resminostat combination, but do not establish comparative efficacy. The RNA-targeting agent TKM-080301 produced modest antitumor activity in 43 patients with Child-Pugh A HCC, with grade 4 thrombocytopenia as the dose-limiting toxicity. LNA-i-miR-221 was administered to only one patient with HCC, precluding disease-specific conclusions.

Preclinical combination strategies have provided mechanistic support but not clinical validation. In cell and animal models, the HDAC inhibitor vorinostat reduced AKT phosphorylation at Ser473 and enhanced cytotoxicity from targeted agents, providing a rationale for combining HDAC and AKT inhibitors. Dual PI3K/HDAC compounds CUDC-907 and BEBT-908 showed greater preclinical antitumor activity than the corresponding single-agent combinations, while DNMT inhibitors can restore PTEN expression and lower AKT activation. The review identifies biomarker selection, treatment sequence, dose adjustment, liver reserve and tumor heterogeneity as central obstacles. Multi-omics markers that combine pathway activity, epigenetic state, genomic background and liver function may eventually guide patient selection, but direct comparative studies across HCC etiologies remain limited. Dedicated HCC trials, longitudinal sampling and validation of nanocarrier-based co-delivery are needed before these approaches can define a clinical standard.

Subject of Research: Bidirectional regulation between PI3K/AKT signaling and epigenetic controls in hepatocellular carcinoma

Article Title: Crosstalk between PI3K/AKT signaling and epigenetic regulation in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities

Article References: Zhang, Z., Liu, J., Lei, G., & Hu, X. (2026). Crosstalk between PI3K/AKT signaling and epigenetic regulation in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities. Frontiers in Cell and Developmental Biology, 14, Article 1975140. https://doi.org/10.3389/fcell.2026.1975140

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1975140

Keywords: hepatocellular carcinoma, PI3K/AKT signaling, epigenetic regulation, DNA methylation, histone modifications, non-coding RNAs, targeted therapy, drug combinations, tumor microenvironment, liver cancer, Crosstalk, between

The review, led by Professor Kefei Yuan of West China Hospital, Sichuan University, and colleagues, was published online in the Chinese Medical Journal on July 30, 2026. It systematically assembles the latest research on how epigenetic regulation and metabolic reprogramming interact in HCC, organizing a sprawling literature into a coherent framework. “A thorough understanding of how epigenetic modifications and metabolic reprogramming interact in HCC is critical for elucidating the mechanisms underlying hepatocarcinogenesis and developing new treatment approaches against HCC,” explains Prof. Yuan, the corresponding author of the review. “In this article, we systematically introduce the molecular basis of each epigenetic modification, then summarize the latest research progress on epigenetic regulation of metabolism in HCC, trying to link these two frontier fields.”

The central insight of the review is that the relationship between metabolism and epigenetics is bidirectional. Metabolic pathways generate small molecules that serve as substrates or cofactors for epigenetic enzymes. Acetyl-CoA, produced from glucose and lipid metabolism, fuels histone acetylation. S-adenosylmethionine (SAM), a product of one-carbon amino acid metabolism, supplies the methyl groups that decorate DNA and histones. Lactate, the end product of the Warburg effect—the phenomenon in which cancer cells preferentially ferment glucose even in the presence of oxygen—has emerged as a signaling molecule in its own right, driving a newly recognized histone modification called lactylation. In this way, the metabolic state of a cell is written directly into its chromatin, the packaged form of DNA that determines which genes are accessible for transcription.

The reverse direction is equally consequential. Epigenetic modifications alter the expression of metabolic enzymes, reinforcing and amplifying the metabolic phenotype of the tumor. Aberrant methylation of promoters controlling metabolic genes can silence or activate entire pathways, shifting cells toward enhanced glycolysis, increased fatty acid synthesis, or reprogrammed amino acid handling. This feedback loop—metabolites shaping epigenetic marks, epigenetic marks shaping metabolic enzymes—creates a self-reinforcing circuit that locks HCC cells into their malignant state and contributes to the construction of a tumor-promoting microenvironment. The review organizes this crosstalk around five major types of epigenetic modification, each with distinct connections to metabolism.

The first is DNA methylation, which shows bidirectional crosstalk with multiple metabolic pathways. On one side, aberrant methylation of metabolic gene promoters drives changes in glycolysis, lipid synthesis, and amino acid metabolism, effectively rewriting the tumor’s metabolic instruction manual. On the other side, metabolic intermediates such as SAM, derived from one-carbon metabolism, provide the raw material for DNA methylation itself, closing the loop. This means that nutritional state, enzyme availability, and flux through one-carbon metabolism can all influence which genes are silenced or expressed, and those expression changes in turn reshape metabolism further.

The second is RNA methylation, particularly N6-methyladenosine (m6A), the most abundant internal modification of messenger RNA in mammalian cells. The review describes how m6A fine-tunes the expression of metabolic enzymes through a cast of regulatory proteins: “writers” such as METTL3 that install the mark, “erasers” such as FTO that remove it, and “readers” such as YTHDFs and IGF2BPs that interpret it and determine the fate of the modified transcript. This dynamic system controls key metabolic processes in HCC, including glycolysis, lipid synthesis, and amino acid metabolism, allowing tumor cells to adjust enzyme production rapidly in response to shifting conditions without altering the underlying DNA sequence.

The third category is non-coding RNAs, which form a multi-layered regulatory network. MicroRNAs directly target the messenger RNAs of metabolic enzymes, dampening or eliminating their translation. Circular RNAs act as sponges that sequester microRNAs, relieving their inhibitory effects, and some can even encode functional peptides. Long non-coding RNAs operate through yet other mechanisms: they interact with proteins, remodel chromatin, or stabilize metabolic enzymes, thereby influencing metabolic pathways at multiple levels simultaneously. The sheer diversity of these RNA species means that a single metabolic pathway in HCC may be regulated by dozens of non-coding RNAs acting in concert, creating redundancy that can frustrate single-target therapies but also offering multiple points of intervention.

The fourth is histone modification, the family of chemical tags on chromatin proteins that includes methylation, acetylation, lactylation, phosphorylation, and ubiquitination. These modifications integrate metabolic signals directly into transcriptional programs. Histone acetylation depends on acetyl-CoA derived from glucose and lipid metabolism, meaning that a cell burning sugar at high rates is chemically primed to open up its genes. Histone methylation depends on SAM from amino acid metabolism, linking nitrogen and one-carbon metabolism to gene expression. Perhaps most striking is lactylation, an emerging modification in which lactate—the very molecule produced by the Warburg effect—is attached to histones, directly coupling glycolytic flux to gene regulation. The review also flags RNA editing as a fifth mechanism, predominantly adenosine-to-inosine (A-to-I) editing mediated by the enzyme ADAR1, which contributes to metabolic reprogramming by altering key genes involved in polyamine metabolism and oxidative stress responses.

What elevates this review beyond a descriptive catalog is its therapeutic framing. The epigenetic-metabolism axis, the authors argue, represents a promising target for drug development. Preclinical studies have shown that targeting DNA methyltransferases, histone modifiers, or non-coding RNAs can reverse metabolic reprogramming and suppress tumor growth. Inhibitors of DNMT1, a DNA methyltransferase, and of histone methyltransferases have demonstrated anti-tumor effects in HCC models. Meanwhile, nanoparticle-mediated delivery of small interfering RNAs targeting metabolic enzymes has shown efficacy in reducing tumor burden in preclinical settings. “Given that epigenetic mechanisms drive metabolic reprogramming essential for HCC survival and drug resistance, targeting this axis theoretically could overcome chemoresistance,” notes Prof. Yuan. “However, promising preclinical candidates have not yet advanced to clinical trials, underscoring the need for further interdisciplinary research.”

The authors are candid about the gaps that remain. The specific effects of metabolites such as cholesterol, ethanol, and alpha-ketoglutarate on DNA methylation require further exploration, a question with direct relevance given that alcohol exposure and lipid dysregulation are major risk factors for liver disease. The relationship between histone modifications and amino acid metabolism remains unclear, as does the role of ketone body metabolism in histone acetylation and the involvement of histone demethylases in metabolic reprogramming. These unresolved questions define the research agenda for the field. What is already clear, however, is that the epigenetic-metabolic crosstalk in HCC is not a side effect of cancer but a central organizing principle of it—a bidirectional network in which every metabolic choice a tumor cell makes is recorded in its chromatin, and every epigenetic mark reshapes its metabolism. Untangling that loop, the review suggests, may be the key to therapies that do not merely attack liver cancer cells but dismantle the regulatory logic that sustains them.

Subject of Research: The bidirectional crosstalk between epigenetic regulation and metabolic reprogramming in hepatocellular carcinoma

Article Title: New review in Chinese Medical Journal illuminates the crosstalk between epigenetics and metabolism in hepatocellular carcinoma

Article References: New review in Chinese Medical Journal illuminates the crosstalk between epigenetics and metabolism in hepatocellular carcinoma. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: hepatocellular carcinoma, epigenetics, metabolic reprogramming, DNA methylation, RNA methylation, m6A, non-coding RNAs, histone modification, lactylation, Warburg effect, cancer metabolism, Chinese Medical Journal

Epigenetics refers to the layer of molecular control that sits above the DNA sequence itself. Cells in the developing lung carry the same genome, yet an alveolar epithelial cell, a vascular endothelial cell and an airway smooth muscle cell behave in radically different ways because of chemical tags that switch genes on or off. The review centers on three principal mechanisms. DNA methylation, the addition of methyl groups to cytosine bases, typically silences genes when deposited in promoter regions. Histone modifications, including acetylation and methylation of the protein spools around which DNA winds, loosen or tighten chromatin and thereby control access of the transcriptional machinery. Finally, non-coding RNAs, including microRNAs and long non-coding RNAs, fine-tune gene expression after transcription. Together these systems form a regulatory network that orchestrates the precisely timed program of alveolarization, the formation of the millions of gas-exchange sacs that define a mature lung.

The problem for preterm infants is that this program is interrupted at its most sensitive stage. Alveolar development in humans largely unfolds during the third trimester, exactly the window in which many extremely preterm infants are instead exposed to mechanical ventilation, supplemental oxygen, infection and inflammation. The review synthesizes evidence that these exposures do not merely stall development; they inscribe lasting epigenetic changes that redirect it. Studies in newborn mice have shown that hyperoxia induces measurable epigenetic alterations in lung tissue, and single-cell transcriptomic analyses have mapped how oxygen-induced damage reshapes the developmental trajectories of individual lung cell populations. In human cohorts, epigenome-wide association studies, including the discovery-BPD program, have identified methylation signatures in preterm infants associated with the disease.

Hyperoxia receives particular attention as a mechanistic driver. Oxygen therapy is indispensable for survival, yet excess oxygen generates reactive oxygen species that overwhelm the immature lung’s antioxidant defenses. The review describes a field known as redox epigenetics, in which oxidative stress directly modifies the epigenetic landscape. Reactive species can alter histone post-translational modifications and influence DNA methylation patterns, linking the infant’s oxidative burden to long-term transcriptional states. Experimental work has shown that hyperoxia suppresses histone deacetylase activity in the neonatal lung, upregulates the cell cycle inhibitor p21 and drives cellular senescence, a state of permanent growth arrest that impairs alveolar formation. Other studies have documented hyperoxia-induced changes in redox-sensitive pathways, angiogenic signaling through vascular endothelial growth factor and hypoxia-inducible factors, and cell cycle control, all of which converge on impaired alveolar and vascular growth.

Inflammation adds a second, complementary layer of programming. Chorioamnionitis, postnatal sepsis and ventilator-induced injury all flood the immature lung with inflammatory cytokines, and the review argues that these stimuli can establish a form of epigenetic memory. In immune cells, inflammatory exposures can produce trained immunity, a state in which innate immune cells respond more vigorously to later challenges because of persistent chromatin remodeling. In the lung, cytokine-mediated epigenetic remodeling may explain why chronic inflammation and defective repair persist in bronchopulmonary dysplasia even after the inciting insult has resolved. Prenatal inflammatory exposures have been shown in animal models to program lung development by modulating mesenchymal fibroblasts in time- and dose-dependent patterns, suggesting that the epigenetic clock of the lung can be reset before birth.

Pharmacologic interventions occupy a more ambiguous position in this framework. Antenatal corticosteroids such as betamethasone are a cornerstone of modern perinatal care, accelerating lung maturation and reducing neonatal mortality. Yet the review highlights evidence that glucocorticoid exposure induces epigenetic changes that are both sex-specific and tissue-specific, acting on the placenta and on hypothalamic-pituitary-adrenal axis-related pathways. Studies have linked glucocorticoid exposure to alterations in epigenetic age in preterm infants and in human lung fibroblasts and neuronal cells. Postnatal steroids, while effective in facilitating extubation, carry well-documented risks for neurodevelopment, and the review situates these clinical trade-offs within the same programming logic: a drug that beneficially accelerates one developmental program may simultaneously leave epigenetic marks elsewhere in the body.

One of the most striking themes is sexual dimorphism. The epigenetic response to hyperoxia in the neonatal lung has been shown to differ between males and females, and sex-dependent transcriptomic changes have been documented in experimental models of the disease. This may help explain the well-recognized clinical observation that male preterm infants fare worse across many neonatal outcomes. The review also extends the framework beyond the lung itself, describing lung-brain-immune interactions in which perinatal hyperoxia and inflammation produce systemic effects, and pointing to epigenetic associations in stress-axis genes related to both bronchopulmonary dysplasia and antenatal steroid exposure. In this model, early-life exposures shape not only lifelong respiratory outcomes but extra-pulmonary ones as well.

The long-term consequences of this programming are increasingly documented. Adult survivors of bronchopulmonary dysplasia show reduced pulmonary reserve, accelerated lung aging and heightened vulnerability to respiratory illnesses across the lifespan, including airflow obstruction resembling early chronic obstructive pulmonary disease. The review proposes that these outcomes reflect epigenetically programmed lung phenotypes: lungs built with fewer alveoli, a simplified vasculature and senescent cell populations that age faster than they should. On the question of whether these marks can be transmitted to the next generation, the authors are careful. Evidence for transgenerational epigenetic inheritance in humans remains limited, and inherited susceptibility to respiratory disease is plausible but unproven. Animal studies demonstrate that such inheritance is mechanistically possible, but extrapolating to human clinical medicine would be premature.

The translational implications are where the review aims to change practice. If bronchopulmonary dysplasia is a disease of biological memory, then the epigenome becomes both a diagnostic target and a therapeutic one. The authors identify the validation of epigenetic biomarkers as a priority: methylation signatures measurable in cord blood or saliva could, in principle, identify high-risk infants within days of birth, enabling earlier and more individualized intervention. Epigenetic maturity scores derived from saliva have already been associated with gestational age at birth, and epigenetic maturity has been linked to respiratory morbidity in preterm infants, providing proof of concept. Longitudinal multi-omics cohort studies that follow infants from the neonatal period into adulthood are flagged as essential to connect early molecular signatures with lifelong outcomes.

Therapeutic possibilities are emerging but remain cautious. Experimental strategies that target the epigenetic machinery, including histone deacetylase inhibitors such as valproic acid, DNA methyltransferase inhibitors, and compounds that boost antioxidant pathways such as the Nrf2 activator dimethyl fumarate, have shown benefit in animal models of the disease. Yet the review emphasizes that the epigenome is not a simple switchboard: indiscriminate manipulation could disrupt developmental programs that are working correctly, and current methodological limitations, including tissue specificity and the difficulty of distinguishing cause from consequence in methylation studies, temper expectations. What the framework offers now is a unifying lens. By integrating hyperoxia, inflammation, pharmacologic exposures and microbiome alterations within a developmental-origins epigenetic model, the authors transform bronchopulmonary dysplasia from a static diagnosis defined by oxygen dependence at thirty-six weeks into a dynamic, mechanistically grounded account of how the first days of life can echo across decades of respiratory health.

Subject of Research: Epigenetic mechanisms linking early-life exposures to persistent lung disease in bronchopulmonary dysplasia

Article Title: Epigenetic programming in bronchopulmonary dysplasia: a framework linking early-life exposures to persistent lung disease—a narrative review

Article References: Rocha, G. M., Amaral, R. S., & Bhandari, V. (2026). Epigenetic programming in bronchopulmonary dysplasia: a framework linking early-life exposures to persistent lung disease—a narrative review. Pediatric Research. https://doi.org/10.1038/s41390-026-05417-2

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05417-2

Keywords: bronchopulmonary dysplasia, epigenetics, DNA methylation, histone modifications, non-coding RNAs, hyperoxia, prematurity, lung development, inflammation, trained immunity, corticosteroids, biomarkers

Autophagy is far more than cellular housekeeping. It is a dynamic, evolutionarily ancient stress-response pathway that cells deploy when nutrients are scarce, when mitochondria are damaged, or when misfolded proteins accumulate. Mechanistically, the process begins when the ULK1 complex, regulated by the nutrient-sensing kinase mTORC1, initiates formation of a double-membraned phagophore. Beclin-1 and the VPS34 lipid kinase then generate phosphatidylinositol-3-phosphate to drive membrane expansion, while Atg12-Atg5 conjugates and Atg8-family proteins such as LC3 decorate the growing autophagosomal membrane. The completed autophagosome travels along dynein motor tracks to fuse with lysosomes, where its cargo is enzymatically dismantled and its building blocks returned to the cytoplasm for reuse.

In bone, this recycling pathway is not a background utility but a central regulator of cellular identity and survival. The review surveys evidence that autophagy functions distinctly in each of the four major bone cell types. In osteoclasts, the giant multinucleated cells that dissolve mineralized matrix, autophagy proteins contribute to the secretory machinery that builds the ruffled border, the specialized resorptive apparatus through which the cell pumps acid and proteases onto bone surfaces. In osteoblasts, the bone-forming cells, autophagy supports the enormous biosynthetic burden of producing collagen and mineral, and mice lacking autophagy in the osteoblast lineage develop low bone mass. In osteocytes, the embedded mechanosensory cells that orchestrate remodeling, autophagy declines with aging, and its experimental suppression in mice produces a skeletal phenotype that mimics accelerated aging.

Bone marrow mesenchymal stem cells add another dimension, because their fate determines whether the skeleton gains or loses material. These progenitors can differentiate into osteoblasts or into adipocytes, and in osteoporosis the balance tips toward fat. Studies cited in the review show that autophagy maintains the osteogenic potential and vitality of these stem cells, protecting them against the estrogen deficiency that drives postmenopausal bone loss, and that promoting autophagy in stem cells derived from osteoporotic vertebrae enhances their differentiation into bone-forming cells. Conversely, autophagy also guards against cellular senescence during skeletal aging, positioning the pathway as a guardian of the bone-forming reservoir itself.

Enter the non-coding RNAs, a diverse family of RNA molecules that are transcribed from the genome but never translated into proteins. MicroRNAs, roughly 20 to 22 nucleotides long, bind complementary sequences in messenger RNAs and silence them. Long non-coding RNAs, which can span thousands of nucleotides, act as epigenetic modulators, scaffolds and decoys. Circular RNAs, covalently closed loops generated by back-splicing, are exceptionally stable and often function as molecular sponges that sequester microRNAs. Together these molecules form competing endogenous RNA networks in which lncRNAs and circRNAs soak up microRNAs, thereby releasing the messenger RNAs those microRNAs would otherwise repress. It is within these networks, the review argues, that autophagy in bone cells is fine-tuned.

The mechanistic examples are striking. MicroRNA-20a suppresses the autophagy protein ATG16L1 during hypoxia-induced osteoclast differentiation, thereby influencing how much bone gets resorbed. MicroRNA-199a-3p mediates estrogen’s effects on autophagy in osteocyte-like cells through the IGF-1/mTOR pathway, linking a sex hormone directly to the recycling machinery. MicroRNA-155 induces autophagy in osteoclasts by targeting a component of inflammatory signaling, while microRNA-152-5p suppresses osteogenic differentiation by restraining ATG14-mediated autophagy in mesenchymal stem cells. On the long non-coding RNA side, SNHG14 activates autophagy through the miR-493-5p/Mef2c axis to slow osteoporosis progression, TUG1 promotes osteogenic differentiation via the AMPK/mTOR/autophagy pathway, and NEAT1 appears in multiple networks, including a competing endogenous RNA circuit involving miR-466f-3p that governs osteoblast autophagy.

Circular RNAs bring their own twists. Exosomal circHIPK3 released from bone marrow mesenchymal stem cells promotes osteogenic differentiation of target cells via mitophagy, the selective autophagic clearance of damaged mitochondria. Circ_0026827 sponges miR-188-3p to activate Beclin1 and RUNX1 signaling in stem cell differentiation, while circCDK8 regulates osteogenic differentiation and apoptosis under hypoxic conditions by inducing endoplasmic reticulum stress and autophagy. Perhaps most provocatively, a recent study cited in the review shows that Staphylococcus aureus, the bacterium behind devastating bone infections, blocks host autophagy through a circSyk/miR-5106/Sik3 axis, demonstrating that pathogens have learned to hijack precisely these RNA circuits.

The therapeutic implications are considerable, though the review is careful to frame them as emerging rather than established. Because individual microRNAs can be inhibited with antagomirs or mimicked with synthetic duplexes, and because lncRNAs and circRNAs can be targeted with antisense oligonucleotides or small interfering RNAs, the ncRNA-autophagy axes offer druggable nodes upstream of the autophagy core machinery. Natural compounds are already being tested along these lines: luteolin inhibits dexamethasone-induced osteoporosis by activating autophagy through the miR-125b-5p/SIRT3/AMPK/mTOR axis, and traditional herbal extracts appear to inhibit osteoclast autophagy by degrading miR-199. Delivery remains the central challenge, and the review highlights extracellular vesicles, including engineered exosomes loaded with therapeutic RNA and guided by magnetic nanoparticles, as well as reducible nanoparticles designed to transfect hard-to-transfect cells, as promising vehicles for carrying RNA drugs into bone tissue.

What makes this synthesis compelling is its reframing of osteoporosis as a disease of misregulated cellular recycling, not merely of imbalanced remodeling. Estrogen deficiency, glucocorticoid excess, oxidative stress and aging all converge on autophagy, and the non-coding RNA networks appear to be the dials through which these systemic insults are translated into cell-type-specific changes in bone homeostasis. The authors, whose work was supported by the Jiangxi Provincial Natural Science Foundation and related regional programs, emphasize that much of the evidence comes from cell culture and rodent models, and that dose, timing and cell-type specificity will determine whether manipulating these axes helps or harms. Still, the direction is clear: if the next generation of osteoporosis therapies can learn to speak the language of non-coding RNAs, they may finally target the disease at the level where aging itself writes its signature into the skeleton.

Subject of Research: Regulation of autophagy by non-coding RNAs in osteoporosis pathogenesis and therapy

Article Title: Non-coding RNAs regulating autophagy in Osteoporosis: mechanistic insights and therapeutic potential

Article References: Wang, X., Cai, Y., Liu, R., Xiao, Y., Liu, W., & Zhao, K. (2026). Non-coding RNAs regulating autophagy in Osteoporosis: mechanistic insights and therapeutic potential. Molecular Biology Reports, 53(1), Article 1711. https://doi.org/10.1007/s11033-026-12930-4

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12930-4

Keywords: osteoporosis, autophagy, non-coding RNAs, microRNAs, long non-coding RNAs, circular RNAs, osteoblasts, osteoclasts, osteocytes, mesenchymal stem cells, bone homeostasis, RNA therapeutics

The scale of RNA activity in plant cells is staggering. Eukaryotic genomes undergo pervasive, genome-wide transcription, generating far more RNA than is needed to encode proteins. These molecules are anything but silent players, the authors emphasize. Their activities are determined not only by their nucleotide sequences but also by multiple regulatory layers, including processing, turnover, chemical modifications, and three-dimensional folding, each contributing critically to how a plant ultimately looks and performs. Over the past decade, high-throughput sequencing, single-molecule sequencing, and precise genome editing have propelled plant RNA biology forward, deepening understanding of RNA regulatory mechanisms and functional networks to a degree that would have been unthinkable a generation ago.

The research paradigm itself has shifted. Plant RNA biology long centered on the model plant Arabidopsis thaliana, a small weed in the mustard family that has served as the workhorse of plant genetics for decades. The review documents how the field has now expanded to a wide range of vital crops, including rice, maize, and wheat. This migration from model organism to staple crop matters enormously for agriculture, because insights into RNA regulatory networks translate directly into genetic resources for crop improvement, including stress-resistant breeding, quality enhancement, and yield promotion. In-depth dissection of these intricate networks, the authors argue, improves the theoretical framework of plant molecular biology while providing critical foundations for applied breeding programs.

The review is structured into eight progressive modules that trace the regulatory mechanisms and agricultural potential of plant RNAs step by step. The first section follows the life cycle of messenger RNA, from its birth through splicing and 3-prime end formation to its eventual degradation. Alternative splicing, particularly intron retention, and 3-prime end processing emerge as key mechanisms shaping transcriptome diversity in plants. The authors also detail the 5-prime-to-3-prime and 3-prime-to-5-prime decay pathways that precisely regulate transcript stability, along with the sophisticated quality control systems that safeguard protein synthesis. These include nonsense-mediated decay, no-go decay, and nonstop decay, surveillance mechanisms that eliminate aberrant transcripts before they can wreak havoc on the cell.

Perhaps the most conceptually striking section redefines the biological functions of classical housekeeping non-coding RNAs, including ribosomal RNAs, transfer RNAs, small nucleolar RNAs, and small nuclear RNAs. For years, these molecules were viewed as humble infrastructure, participating only in translation and splicing. The review confirms that they do far more: they can respond to environmental signals, generate functional small RNAs, and participate in plant developmental regulation, stress adaptation, chromatin remodeling, and gene silencing. This reframing suggests that even the most familiar RNA species in the cell harbor regulatory capacities that remain largely untapped in crop science, a finding with significant implications for how researchers screen for agriculturally useful RNA functions.

Small RNAs and long non-coding RNAs receive their own dedicated treatments. The small RNA section elucidates the biogenesis pathways and action modes of microRNAs and various classes of small interfering RNAs, revealing that these molecules regulate plant growth, development, and stress responses through target cleavage, translational repression, and DNA methylation. The non-cell-autonomous movement of small RNAs between cells, and their cross-kingdom transport, are identified as core links connecting developmental regulation with stress adaptation. The long non-coding RNA section overturns the early perception of these transcripts as transcriptional noise, concluding that they participate in flowering, reproduction, root development, and stress responses through multiple strategies, including recruiting chromatin modification complexes, sequestering microRNAs, modulating protein activity, and even encoding functional small peptides.

Two emerging fields receive forward-looking coverage. The first is RNA higher-order structure, where cutting-edge in vivo structural profiling technologies are uncovering how RNA secondary structures influence splicing, translational regulation, and temperature sensing. The review highlights the value of TPP riboswitches and ribosnitches, sequence-variation-mediated RNA structural remodeling elements, in regulating crop agronomic traits. The second is the rapidly expanding field of RNA chemical modifications. The authors systematically summarize non-canonical cap structures such as m7G and NAD, and internal modifications including m6A, m5C, and ac4C, elaborating the writer, eraser, and reader protein systems that install, remove, and recognize these chemical tags. RNA modifications, they conclude, constitute a crucial post-transcriptional regulatory layer that extensively modulates plant development, immunity, and stress responses.

The agricultural payoff is where the review becomes most concrete. Artificial modification of microRNAs and long non-coding RNAs can effectively enhance crop yield, stress tolerance, and nutrient use efficiency. Beyond endogenous RNA manipulation, RNA interference technologies offer innovative and eco-friendly strategies for protecting crops from diseases and pests. Spray-induced gene silencing allows farmers to apply double-stranded RNA directly to plants, while microbe-induced gene silencing harnesses beneficial microorganisms to deliver silencing signals. Cross-kingdom RNAi mechanisms, in which small RNAs move between species, underpin these approaches. Together, they provide green alternatives to traditional chemical pesticides, overcoming the environmental limitations of conventional crop protection methods at a time when sustainable agriculture has become an urgent global priority.

The final module looks ahead, identifying the core challenges and opportunities that will define the next phase of plant RNA biology. The authors propose the necessity of dissecting the synergistic mechanisms among diverse RNA regulatory pathways, since no single RNA class operates in isolation. They call for advancing single-cell-level research on RNA dynamics, which would reveal how regulatory networks differ across the specialized cell types that make up plant tissues. They also point to ncRNA editing, RNA synthetic biology, novel RNAi technologies, and multi-tool combined gene editing systems as sources of brand-new technical support for precision plant breeding and the development of green, sustainable agriculture.

Taken as a whole, the review bridges a persistent gap between fundamental theoretical research on plant RNAs and practical agricultural application. It provides important theoretical references and frontier directions for deciphering plant RNA regulatory networks, addressing food security, and promoting the high-quality development of sustainable agriculture. The collaboration of sixteen experts across institutions including Tsinghua University, Sun Yat-sen University, Southern University of Science and Technology, the Chinese Academy of Sciences, Peking University, and Fudan University reflects the maturity the field has reached. As climate change intensifies pressure on global crop production, the ability to read, understand, and ultimately engineer the RNA regulatory landscape of plants may prove one of the most consequential tools in modern agricultural science.

Subject of Research: RNA regulatory mechanisms in plants and their application to crop improvement

Article Title: New comprehensive review maps the RNA regulatory landscape in plants

Article References: New comprehensive review maps the RNA regulatory landscape in plants. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: plant RNA biology, non-coding RNAs, microRNAs, RNA modifications, m6A, RNA interference, alternative splicing, lncRNAs, small RNAs, crop improvement, food security, sustainable agriculture

The research, led by Xiaoyu Zhang, Kaiyun Fu, and colleagues at the Xinjiang Academy of Agricultural Sciences together with collaborators at the Chinese Academy of Sciences, focused on a class of regulatory molecules known as competing endogenous RNAs, or ceRNAs. The ceRNA hypothesis proposes that different RNA transcripts, including messenger RNAs that encode proteins as well as non-coding RNAs that do not, can communicate with one another by competing for the same microRNA molecules. MicroRNAs are short RNA fragments that bind to complementary sequences on target transcripts and suppress their activity. When a non-coding RNA sponges up a shared microRNA, it effectively shields other transcripts from repression, creating a regulatory network in which abundance of one RNA can indirectly control the expression of many others.

To map this network in a starving insect, the team performed whole-transcriptome sequencing on T. absoluta larvae under two conditions: larvae feeding on fresh tomato leaves and larvae subjected to starvation. By comparing the complete repertoire of expressed molecules between the two groups, they identified a striking number of differentially expressed transcripts. In total, the analysis revealed 46 differentially expressed microRNAs, 2,143 differentially expressed messenger RNAs, 391 differentially expressed long non-coding RNAs, and 1,635 differentially expressed circular RNAs. Circular RNAs, which are formed when RNA strands are joined head-to-tail into closed loops, are particularly stable molecules and have emerged as potent microRNA sponges in many organisms, making their large-scale differential expression especially noteworthy.

With these differential expression profiles in hand, the researchers constructed putative regulatory networks linking the different RNA classes. Using computational prediction of binding sites combined with expression correlation analyses, they built both lncRNA–miRNA–mRNA and circRNA–miRNA–mRNA interaction networks. These networks represent hypotheses about which non-coding RNAs might be titrating away which microRNAs, and consequently which protein-coding genes might be released from repression or placed under additional control during starvation. The scale of the networks suggests that ceRNA-mediated crosstalk is a substantial component of the leafminer’s stress response rather than a marginal curiosity.

Functional enrichment analysis of the genes embedded in these networks provided the first clues about what the regulation is actually accomplishing. The differentially expressed messenger RNAs, the predicted microRNA target genes, and the host genes that give rise to circular RNAs were predominantly associated with chitin metabolism, lipid catabolism, fatty acid biosynthesis, and detoxification pathways. Each of these categories makes biological sense for a starving insect. Chitin is the structural polymer of the insect cuticle and gut lining, and its remodeling may reflect the physiological strain of fasting. Lipid catabolism and fatty acid metabolism are the classic fallback energy pathways when dietary carbohydrates and proteins run out, allowing the animal to mobilize stored fat reserves. Detoxification pathways, meanwhile, may help the insect cope with the metabolic byproducts of starvation or maintain its chemical defenses.

Deeper pathway analysis using the Kyoto Encyclopedia of Genes and Genomes reinforced this metabolic picture. Significant enrichment was observed in AMPK signaling, a conserved cellular energy-sensing pathway that switches on when intracellular energy levels fall and orchestrates the shift from energy consumption to energy production. Insulin signaling was also enriched, reflecting its central role in coordinating growth, nutrient storage, and mobilization in response to nutritional state. The biosynthesis of unsaturated fatty acids appeared as another significantly enriched pathway, consistent with the idea that starving larvae adjust the composition of their membrane lipids and fuel reserves to survive the crisis. Together, these pathways sketch a coherent strategy: sense the energy deficit, reroute metabolism toward stored fats, and adjust cellular infrastructure accordingly.

Perhaps the most striking single finding is the identification of two microRNAs, miR-6497a and miR-6498-5p, as putative key regulatory hubs within the ceRNA network. These two microRNAs were predicted to interact with multiple differentially expressed long non-coding RNAs, circular RNAs, and messenger RNAs simultaneously, placing them at the center of a dense web of potential crosstalk. In the ceRNA framework, a hub microRNA whose binding is contested by many sponges can exert broad, condition-dependent control over entire functional modules. If experimental work confirms these interactions, miR-6497a and miR-6498-5p would represent master switches that help determine how the leafminer’s metabolism is reconfigured when food disappears.

The study’s significance extends well beyond basic biology. Tuta absoluta, native to South America, has spread rapidly across Europe, Africa, and Asia since its initial invasions and remains a persistent threat to tomato production worldwide. Its capacity to survive unfavorable conditions, including gaps in food availability between crops or during dispersal, contributes to its invasive success and complicates control efforts. Current management relies heavily on chemical insecticides, against which the species has already evolved resistance to multiple modes of action. This has intensified interest in RNA interference as an alternative: double-stranded RNA molecules can be designed to silence essential pest genes with high specificity, and several RNAi-based products are in development for agricultural use. The ceRNA networks described in this study offer a catalog of candidate targets, particularly the hub microRNAs and the non-coding RNAs that regulate them, whose disruption could impair the pest’s ability to withstand starvation and other stresses encountered in the field.

The work also adds to a growing appreciation that non-coding RNAs are not background noise but active participants in how organisms respond to their environments. Long non-coding RNAs and circular RNAs have been implicated in stress responses in many species, but their roles in agricultural insect pests remain poorly charted. By integrating all four major RNA classes in a single analysis, the researchers demonstrated a methodology that other pest biologists can replicate, connecting transcriptome-wide discovery with functional interpretation. The authors caution that the networks are putative, resting on computational prediction and expression correlation, and that experimental validation will be needed to confirm individual interactions and to test whether manipulating these RNAs genuinely compromises the insect’s stress tolerance.

Even so, the study marks an important step in the molecular dissection of one of agriculture’s most notorious adversaries. It shows that when the tomato leafminer goes hungry, it does not simply slow down; it activates a coordinated, multi-layered RNA regulatory program that touches energy sensing, fat metabolism, structural remodeling, and detoxification all at once. Understanding that program in detail, and learning to break it, could give crop scientists a much-needed new angle of attack against a pest that has repeatedly outmaneuvered conventional control methods. For now, the humble non-coding RNA molecules once dismissed as transcriptional clutter have emerged as promising new players in the ongoing arms race between farmers and the insects that threaten their harvests.

Subject of Research: ceRNA regulatory networks in Tuta absoluta adaptation to starvation stress

Article Title: Integrated whole‑transcriptome analysis reveals ceRNA regulatory networks underlying Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) adaptation to starvation stress

Article References: Zhang, X., Wen, Y., Jia, Z., Wang, X., Wu, J., Ding, X., Guo, W., & Fu, K. (2026). Integrated whole‑transcriptome analysis reveals ceRNA regulatory networks underlying Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) adaptation to starvation stress. BMC Genomics. https://doi.org/10.1186/s12864-026-13273-x

Image Credits: AI Generated

DOI: 10.1186/s12864-026-13273-x

Keywords: Tuta absoluta, tomato leafminer, ceRNA, non-coding RNAs, microRNAs, lncRNAs, circRNAs, starvation stress, transcriptomics, AMPK signaling, lipid metabolism, RNAi pest control