Researchers at Wuhan Tongji Hospital set out to test whether time-restricted feeding, or TRF, could delay vascular aging in mice. The regimen they chose was demanding by human standards: animals had access to food for only six hours each day, aligned with their nocturnal circadian rhythm, while water remained freely available. Crucially, the mice did not lose weight. Caloric intake, body weight, fasting blood glucose, and fat mass were all essentially unchanged between the restricted eaters and mice eating whenever they pleased. Whatever benefit TRF conferred, it was not a simple consequence of eating less.

To model vascular aging, the team implanted pumps that delivered angiotensin II, a hormone that at sustained elevated levels drives hypertension, vascular wall thickening, elastic fiber fragmentation, and collagen deposition—a constellation of changes that mirrors what happens to human arteries over decades. After four weeks of infusion, mice on a normal diet showed markedly elevated systolic, diastolic, and mean blood pressure, along with increased pulse wave velocity, the gold-standard clinical measure of arterial stiffness. Their aortas dilated, their intima-media thickness increased, and their vascular walls showed the disorganized collagen and degraded elastic fibers characteristic of aged vessels under the electron microscope.

The restricted-fed mice told a strikingly different story. TRF significantly blunted the angiotensin II–induced rise in blood pressure, reduced aortic stiffness, and preserved the structural integrity of the vessel wall. At the molecular level, the intervention suppressed the upregulation of p53, p21, and p16—canonical markers of cellular senescence—in the aorta. The heart benefited as well: echocardiography showed better ejection fraction and fractional shortening, and histology revealed less myocardial fibrosis and cardiomyocyte hypertrophy, suggesting that TRF interrupts the vicious feedback loop in which stiff arteries strain the heart and a failing heart further damages the vasculature.

But the most provocative findings came from the gut. Metagenomic sequencing of fecal samples revealed that TRF reshaped the microbial community, increasing Firmicutes abundance and stabilizing the ratio of Firmicutes to Bacteroidetes, a microbial signature previously associated with aging resilience. When angiotensin II disrupted the microbiota of normally fed mice—depleting Bacteroidetes and enriching Verrucomicrobia—the restricted-fed animals maintained a stable community. TRF also protected the intestinal barrier: goblet cell numbers and mucus reserves were restored, tight junction proteins such as occludin, ZO-1, and MUC2 were preserved, and serum levels of lipopolysaccharide, a pro-inflammatory endotoxin that leaks into circulation when the gut lining fails, were significantly lower.

To prove that these microbial changes were not merely a byproduct of the diet but its actual cause, the researchers turned to germ-free mice. These animals, raised in sterile isolation and lacking any microbiome of their own, received fecal transplants from either normally fed or time-restricted donors. Remarkably, germ-free mice colonized with the TRF microbiota were resistant to angiotensin II–induced hypertension, vascular stiffening, aortic dilation, and pathological cardiac remodeling—despite never having been on the diet themselves. Their endothelium-dependent vasodilation, a key indicator of vascular health, was preserved where transplant recipients of normal microbiota lost it. The gut microbes alone were sufficient to carry the protection.

Metabolomic analysis pointed to the chemical messenger responsible. Fecal levels of short-chain fatty acids—microbial fermentation products known to reinforce barrier integrity, regulate blood pressure, and suppress inflammation—were elevated in the TRF-transplanted animals, with acetic acid showing the largest and most consistent increase. Correlation analyses strengthened the case: fecal acetic acid concentrations tracked positively with colonic tight junction protein expression and negatively with aortic senescence markers, pulse wave velocity, and cardiac fibrosis. Integrated metagenomic and metabolomic data further showed that TRF restored the abundance of genes in acetic acid synthesis pathways, and identified Limosilactobacillus, a lactic acid bacterium, as the key source organism enriched by the feeding schedule.

To test whether acetic acid could substitute for the diet itself, the team gave mice daily sodium acetate gavage alongside angiotensin II infusion. The supplement reproduced nearly all of TRF’s benefits: lower blood pressure, reduced aortic stiffness and dilation, less elastic fiber fragmentation and collagen deposition, improved cardiac function, and a fortified intestinal barrier with restored goblet cells and tight junctions. Conversely, when the researchers wiped out the microbiome with an antibiotic cocktail, TRF’s protective effects on vessels, heart, and gut largely vanished—yet supplementing acetate in these microbe-depleted animals restored blood pressure homeostasis and barrier integrity even though it could not rebuild the microbial community itself. Acetic acid, in other words, sits downstream of the microbiota and is sufficient to carry the signal.

The molecular mechanism traces an elegant path from bacterial metabolite to chromatin. Acetic acid engages GPR43, a G protein–coupled receptor on vascular and cardiac cells, which in turn suppresses the histone deacetylase HDAC3. With HDAC3 held in check, acetylation of histone H4 at lysine 8 rises, opening chromatin in a way that dampens the NLRP3 inflammasome and the pyroptotic cell death pathway it drives, along with the inflammatory cytokines TNF-α, IL-6, and IL-1β. In human umbilical vein endothelial cells exposed to angiotensin II, sodium acetate reversed the senescent phenotype, reduced senescence-associated beta-galactosidase positivity, and restored H4K8 acetylation—confirming that the axis operates in human-relevant cells, not just mouse tissue.

The authors are candid about the study’s limits. All experiments used male mice, leaving open whether females respond similarly given known sex differences in both vascular biology and gut ecology. The angiotensin II model, while well established, captures an accelerated form of vascular aging rather than the slow, multifactorial decline of natural aging, and validation in naturally aged animals is needed. Translating the schedule to humans is also nontrivial: a six-hour feeding window in mice, with their high metabolic rate and shifted circadian phase, roughly corresponds to an eight-to-ten-hour eating window in people, which may still be difficult for elderly patients managing medications, comorbidities, or malnutrition risk. Careful monitoring for hypoglycemia and muscle loss would be essential. Yet the core message stands as one of the most mechanistically complete demonstrations yet that a dietary pattern can slow cardiovascular aging through a defined microbe–metabolite–epigenome pathway. If the findings hold in human trials, the humble gut bacterium and its acidic byproduct may become targets for keeping arteries young—no calorie counting required.

Subject of Research: Time-restricted feeding, gut microbiota remodeling, and acetic acid-mediated delay of cardiovascular aging

Article Title: Time‐Restricted Feeding Delays Cardiovascular Aging by Increasing Acetic Acid Through Remodeling Gut Microbiota

Article References: Liu, M., Luo, M., Huang, Y., Ji, T., Wang, Y., Wang, Q., Huang, J., Jiang, T., Zhang, C., Mi, T., & Cheng, M. (2026). Time‐Restricted Feeding Delays Cardiovascular Aging by Increasing Acetic Acid Through Remodeling Gut Microbiota. Aging Cell, 25(10), Article e70728. https://doi.org/10.1111/acel.70728

Image Credits: AI Generated

DOI: 10.1111/acel.70728

Keywords: time-restricted feeding, vascular aging, gut microbiota, acetic acid, short-chain fatty acids, hypertension, Limosilactobacillus, GPR43, HDAC3, NLRP3 inflammasome, fecal microbiota transplantation, intestinal barrier

Extrachromosomal circular DNA is exactly what the name suggests: small rings of DNA that exist outside the chromosomes, looping free of the linear genome. Unlike chromosomal DNA, these circles can carry intact gene fragments and regulatory elements, and because they replicate independently of the normal cell cycle, they can be amplified rapidly in numbers. That property makes eccDNA a potent engine of oncogene overexpression, a mechanism that has been implicated in drug resistance in several cancers, including notoriously amplified circles carrying the MYC oncogene in neuroblastoma and other tumors. Yet in ovarian cancer, the interplay between eccDNA and the epigenetic machinery that controls gene activity has remained poorly charted territory.

The epigenetic machinery in question centers on histone deacetylases, or HDACs, enzymes that remove acetyl chemical groups from histone proteins around which DNA is wound. When histones are highly acetylated, DNA is more accessible and genes are more active; HDACs strip those acetyl groups away, tightening chromatin and silencing genes. In many cancers, HDAC activity is dysregulated, contributing to the abnormal silencing of tumor suppressors and the miswiring of gene-control networks. HDAC inhibitors, including the drug panobinostat, also known by its code name LBH589, were designed to reverse that silencing and restore normal gene expression patterns in tumor cells.

Panobinostat is a broad-spectrum HDAC inhibitor that has been tested in various hematologic and solid malignancies. The new study set out to ask a question that is often overlooked in drug development: what happens to the eccDNA landscape when a tumor is treated with an epigenetic drug? The answer, according to the team’s experiments, is that the drug does far more than simply reactivate silenced genes. It induces a significant remodeling of the eccDNA population within ovarian cancer cells, with a notable enrichment of circles derived from messenger RNA genes and from long noncoding RNAs, a class of regulatory RNA molecules with their own roles in cancer biology.

To connect this eccDNA remodeling to gene activity, the researchers integrated two powerful genome-wide datasets. The first came from RNA sequencing, which measures the complete set of RNA transcripts produced by the cells and therefore reveals which genes are switched up or down under treatment. The second came from chromatin immunoprecipitation sequencing, or ChIP-seq, targeted at HDAC3, one of the key histone deacetylase enzymes. ChIP-seq identifies the precise genomic locations where HDAC3 binds, marking the genes it directly regulates. By overlaying these maps with the eccDNA data, the team identified a set of 52 oncogenes that are linked to eccDNA, bound by HDAC3, and consistently upregulated by panobinostat treatment.

That convergence of three independent molecular signals, eccDNA presence, HDAC3 binding, and treatment-induced upregulation, is what gives the finding its weight. It suggests that the drug’s inhibition of HDAC3 does not uniformly suppress oncogenic potential. Instead, in at least a subset of genes, blocking HDAC3 appears to coincide with an adaptive activation program in which oncogenes carried or associated with circular DNA become more highly expressed. The authors describe this as an adaptive oncogenic response, a kind of molecular counterpunch thrown by the tumor as the epigenetic pressure of the drug takes hold.

The clinical relevance of these 52 genes was tested using survival analysis across multiple cancer cohorts. The team found that alterations in these oncogenes correlated with worse disease-free survival, meaning that patients whose tumors carried changes in these genes tended to remain cancer-free for shorter periods after treatment. This kind of population-level correlation does not prove causation on its own, but it flags the gene set as a meaningful marker of aggressive disease and provides a rationale for digging deeper into individual members of the group.

One member stood out. LMO2, a gene encoding a transcriptional regulator best known for its roles in blood cell development and, historically, as a gene disrupted in certain leukemias, emerged from the analysis as a novel oncogene in ovarian cancer. The mechanistic work behind this claim is technically detailed but conceptually clear. Supplementary analyses showed that panobinostat increases the levels of H3K27ac, an acetyl mark on histone H3 that signals active regulatory regions, at the promoter-proximal regions of the LMO2 gene, without altering HDAC3 binding at those same sites. In other words, the drug does not move HDAC3 off the DNA; it changes the chemical balance of chromatin in a way that favors LMO2 activation.

Functional experiments reinforced the picture. In TOV-112D, an ovarian cancer cell line used in the study, inhibiting HDAC3 with drugs or knocking the enzyme down with interfering RNAs both led to increased LMO2 expression. Conversely, when the researchers knocked LMO2 down, the cells became more sensitive to panobinostat. That last result is the most consequential: it implies that LMO2 upregulation is not merely a byproduct of treatment but a functional contributor to reduced drug sensitivity. A tumor that can ramp up LMO2 in response to HDAC inhibition may thereby cushion itself against the drug’s effects, and removing that cushion restores vulnerability.

The broader significance of the study lies in its demonstration that epigenetic therapy and the eccDNA layer of cancer genetics are deeply intertwined. HDAC-associated epigenetic regulation, the authors conclude, is connected to eccDNA-linked oncogene activation, and this connection may modulate how ovarian cancer patients respond to HDAC inhibitors. For clinicians, the work suggests a potential combination strategy: pairing HDAC inhibitors with approaches that suppress LMO2 or its downstream effects could prevent the adaptive escape that otherwise undermines treatment. For researchers, the study provides a template for integrating Circle-seq, RNA-seq, and ChIP-seq data to find similar vulnerabilities in other tumor types. The work, supported by funding from the National Natural Science Foundation of China and provincial programs, was conducted with approval from the Animal Welfare Committee of Fudan University Shanghai Cancer Center, and the authors report no competing interests. As the field moves toward therapies that target the nonchromosomal genome, LMO2 now stands as a concrete, testable target in the fight against ovarian cancer’s most stubborn defense mechanisms.

Subject of Research: The interplay between extrachromosomal circular DNA, HDAC3-mediated epigenetic regulation, and oncogene activation in ovarian cancer

Article Title: Integration of eccDNA and transcriptomic landscapes uncovers LMO2 as a therapeutic target in ovarian cancer

Article References: Han, T., Yan, Q., Bu, H., Gan, Y., Shen, X., Li, K., Guan, L., Dong, W., Li, P., Zhao, M., Zhou, X., Gao, B., & Hao, Q. (2026). Integration of eccDNA and transcriptomic landscapes uncovers LMO2 as a therapeutic target in ovarian cancer. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02296-3

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02296-3

Keywords: eccDNA, ovarian cancer, LMO2, HDAC3, panobinostat, epigenetics, oncogene, drug resistance, transcriptomics, ChIP-seq, therapeutic target, Journal of Ovarian Research

The finding matters because gestational diabetes affects a substantial share of pregnancies worldwide and raises risks for both mother and child, including future type 2 diabetes. Previous observational work had already hinted that pregnant women who develop the condition tend to have lower levels of butyrate in their circulation. What remained unclear was whether this deficiency was merely a byproduct of the disease or a genuine driver of it, and if the latter, through which molecular route butyrate might act. The new study set out to answer both questions with a combination of human data, animal experiments and mechanistic work at the level of chromatin.

The clinical arm of the study was a nested case-control analysis that measured serum butyrate and active GLP-1, the glucagon-like peptide-1 hormone released by intestinal cells after meals to stimulate insulin secretion, in pregnant women. The results were striking in their consistency: women who went on to develop gestational diabetes had significantly lower levels of both butyrate and active GLP-1, and this difference was detectable not only in mid-pregnancy, when the condition typically manifests, but already in early pregnancy. That early timing is important, because it suggests that a depleted butyrate-GLP-1 axis precedes the onset of disease rather than simply following from it, raising the possibility of prediction and even prevention.

To test causality, the team turned to a mouse model of gestational diabetes induced by a high-fat diet combined with antibiotics, a regimen that disrupts the gut microbial community and mimics the metabolic disturbances seen in patients. When the animals received a probiotic supplement of Clostridium butyricum, a bacterium renowned for its butyrate production, their metabolic picture improved markedly. Hyperglycaemia eased, insulin resistance declined, and perhaps most intriguingly, the disruption of circadian glucose rhythms that accompanies gestational diabetes was partially corrected. Microbial profiling of the treated animals confirmed that the supplement enriched the community of butyrate-producing bacteria and raised systemic butyrate levels, tying the metabolic benefits directly to the microbial metabolite.

The mechanistic heart of the study lies in the colon. Butyrate has long been known to act as an inhibitor of histone deacetylases, enzymes that remove acetyl groups from histone proteins and, in doing so, keep stretches of DNA tightly packed and transcriptionally silent. When the researchers examined colon tissue from the treated mice, they found that Clostridium butyricum supplementation reduced the abundance of one particular deacetylase, HDAC3, and increased the global acetylation of histone H3 at lysine 27, a chemical mark known as H3K27ac that flags active genes and their regulatory elements. In other words, the microbial metabolite appeared to be physically opening up the genome in intestinal cells.

Which genes were being opened? To find out, the team performed integrated RNA sequencing and H3K27ac chromatin immunoprecipitation sequencing in enteroendocrine cells, the hormone-producing specialists of the gut lining, treated with sodium butyrate and with agents that modulate HDAC3. The multi-omics analysis converged on a single compelling candidate: secretagogin, or SCGN, a calcium-binding protein expressed in enteroendocrine cells. Butyrate enhanced both the transcription of SCGN and the deposition of H3K27ac at its promoter, indicating that the metabolite directly activates the gene through the same epigenetic mechanism. Because SCGN has been implicated in the regulated secretion of peptide hormones, the connection to GLP-1 was an obvious next step.

The functional experiments confirmed it. Treating enteroendocrine cells with butyrate, or knocking down HDAC3 with molecular tools, increased SCGN expression and boosted the secretion of GLP-1. Conversely, when the researchers forced cells to overexpress HDAC3, the SCGN-GLP-1 axis was suppressed, but this suppression could be reversed by co-treatment with butyrate. The epigenetic brake and the microbial metabolite were locked in a push-pull relationship: HDAC3 silences the hormone-secreting programme, and butyrate releases it. This is a textbook example of how a dietary and microbial signal can be translated into a durable change in gene expression, one that ultimately shapes whole-body metabolism.

Genetic validation in living animals provided the final, decisive test. The team used mice that carry only one functional copy of the HDAC3 gene, a condition known as haploinsufficiency, which reduces the protein’s levels without eliminating it entirely. If the benefits of Clostridium butyricum truly flow through HDAC3 inhibition, then animals with less HDAC3 to begin with should gain little from the probiotic. That is precisely what the researchers observed: in HDAC3-haploinsufficient mice, the metabolic improvements and the upregulation of SCGN driven by the bacterium were abolished. The genetic experiment closes the causal loop and rules out the possibility that butyrate works through unrelated pathways.

Taken together, the study delineates what the authors describe as a novel gut microbiota-epigenetic-hormonal axis. Gut bacteria produce butyrate; butyrate inhibits HDAC3 in the intestinal lining; HDAC3 inhibition raises H3K27ac at the SCGN promoter; SCGN activation potentiates GLP-1 secretion; and GLP-1 improves glucose homeostasis for mother and fetus. Each link in this chain was tested independently, from the human correlation through the mouse intervention to the chromatin-level biochemistry and the genetic knockout. The architecture of the pathway is elegant precisely because it is specific: rather than a diffuse anti-inflammatory effect, the metabolite acts on a defined enzyme at a defined genomic target to produce a defined hormonal outcome.

The translational implications are considerable. HDAC3 and the downstream SCGN-GLP-1 pathway now stand as candidate targets for preventing or treating gestational diabetes, whether through probiotic supplementation with butyrate-producing strains such as Clostridium butyricum, dietary strategies that favour butyrate-producing communities, or future drugs that modulate HDAC3 activity in the gut. The authors note that their work was supported by the Beijing Municipal Natural Science Foundation, the National Natural Science Foundation of China and related programmes, and the study was conducted under ethics approvals for both the human cohort and the animal experiments. As with any mouse study, the road to clinical application will require trials in pregnant women, but the early-pregnancy signature of low butyrate and low GLP-1 offers a tantalising window for intervention long before the disease declares itself. For a condition that shapes the lifelong metabolic health of two generations at once, a microbial molecule that rewrites gene expression in the gut may prove to be one of the most consequential discoveries in pregnancy metabolism in years.

Subject of Research: How the gut microbial metabolite butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis

Article Title: The gut microbiota-derived butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis

Article References: Han, W., Zhang, Y., Huang, J., Lu, Y., Yin, X., Zhao, Y., Yuan, X., Yang, R., Zhang, L., Zheng, W., & Li, G. (2026). The gut microbiota-derived butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08720-y

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08720-y

Keywords: gestational diabetes, butyrate, gut microbiota, HDAC3, epigenetics, GLP-1, secretagogin, Clostridium butyricum, histone acetylation, H3K27ac, enteroendocrine cells, insulin resistance

The research, led by Wanqiu Huang and Jinjing Ni together with colleagues at Shanghai Jiao Tong University School of Medicine and collaborating institutions, focuses on a histone modification known as H2BK16ac. This tag refers to the acetylation of lysine 16 on histone H2B, one of the proteins around which DNA is wound. Acetylation of histone tails generally loosens the chromatin structure, making genes more accessible to the transcription machinery. When the researchers examined macrophages infected with Salmonella, they found that this acetylation mark on H2BK16 was actively removed. The deacetylation was carried out by two enzymes, HDAC1 and HDAC3, which strip acetyl groups from histones and thereby tighten chromatin at specific genomic locations.

The consequence of this chromatin tightening was the transcriptional silencing of a gene called Id3, which encodes Inhibitor of Differentiation 3. ID3 is a member of the helix-loop-helix protein family and is known to influence the behavior of various immune cells, but its role in macrophage-mediated antibacterial defense had not been clearly defined. The new study shows that when Salmonella drives H2BK16 deacetylation through HDAC1 and HDAC3, the Id3 gene is switched off, and macrophages lose an important layer of antimicrobial capacity. This finding places ID3 at the center of an infection-induced epigenetic pathway that directly shapes how macrophages respond to bacterial challenge.

To establish that ID3 genuinely strengthens macrophage defenses, the team performed both loss-of-function and gain-of-function experiments. When ID3 was removed or reduced, macrophages showed a weakened inflammatory response and diminished antimicrobial activity. Conversely, when ID3 was increased, macrophages displayed enhanced antibacterial function. These results demonstrate that ID3 is not a passive bystander in the infection response but an active contributor to the macrophage arsenal against invading bacteria.

The mechanistic heart of the study lies in how ID3 controls the expression of another protein, Z-DNA binding protein 1, commonly abbreviated as ZBP1. ZBP1 is a sensor that recognizes certain nucleic acid structures and participates in immune signaling. The researchers discovered that a transcription factor called E2A binds to the ZBP1 gene and represses its transcription. ID3 counteracts this repression by sequestering E2A, effectively pulling it away from the ZBP1 promoter. With E2A occupied by ID3, the ZBP1 gene is free to be transcribed, and macrophages maintain robust ZBP1 expression. This sequestration mechanism reveals a precise molecular handoff in which ID3 acts as a decoy to relieve transcriptional braking on an antimicrobial effector gene.

The in vivo relevance of this circuit was tested in mice engineered to lack Id3 specifically in myeloid cells, the lineage that includes macrophages. When these myeloid-specific Id3-deficient mice were infected with Salmonella, they carried higher bacterial burdens and suffered greater pathological damage than control animals. This outcome confirms that the ID3-ZBP1 axis is not merely a cell-culture curiosity but a functional component of antibacterial immunity in living organisms. The data suggest that the integrity of this epigenetic pathway determines how effectively the host can contain systemic bacterial spread.

Perhaps the most translational aspect of the study involves a pharmacological intervention. The researchers treated infected mice with MS-275, an inhibitor of histone deacetylases that targets HDAC1 among other class I enzymes. Administration of MS-275 restored the H2BK16ac mark, reactivated the Id3 gene, and thereby rebuilt the ID3-ZBP1 signaling axis. In practical terms, the drug reversed the epigenetic silencing that Salmonella had imposed on macrophages. Mice receiving this treatment showed amelioration of systemic Salmonella infection, demonstrating that pharmacologically reopening the chromatin at Id3 can translate into meaningful protection against bacterial disease.

These findings carry several implications for the broader field of infection biology. First, they establish that pathogens do not merely evade immune detection; they actively reshape the epigenetic landscape of host immune cells to disable specific defense genes. The Salmonella-driven deacetylation of H2BK16 represents a concrete example of how bacterial infection can hijack the host’s own chromatin-modifying enzymes to silence protective transcriptional programs. Second, the study identifies ID3 as a previously underappreciated regulator of macrophage immunity, bridging histone acetylation status to the expression of a nucleic acid sensor involved in antimicrobial signaling. Third, the demonstration that an HDAC inhibitor can restore this axis in vivo suggests a therapeutic window in which epigenetic drugs, originally developed for oncology, might be repurposed as adjunct treatments for severe bacterial infections.

The work also raises questions that will likely drive future research. It remains to be seen whether other pathogens employ similar strategies to silence Id3 or related immune regulators through histone deacetylation. The precise kinetics of HDAC1 and HDAC3 recruitment to the Id3 locus during infection, and whether additional chromatin marks cooperate with H2BK16ac in this process, are areas that warrant deeper investigation. Furthermore, because ZBP1 has been implicated in antiviral as well as antibacterial pathways, the ID3-E2A-ZBP1 circuit could have relevance beyond Salmonella, potentially influencing how macrophages respond to a wider spectrum of infectious threats. The study by Huang, Ni, and colleagues thus opens a new line of inquiry into how epigenetic therapies might bolster innate immunity at a time when antibiotic resistance continues to limit conventional treatment options.

Subject of Research: Infection-driven epigenetic regulation of macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis

Article Title: Infection-driven epigenetics modulate macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis

Article References: Huang, W., Ni, J., Tang, H., Chen, Y., Zhou, T., Yu, J., Wang, Z., Wen, B., Yan, H., Wang, C., Tao, J., Lu, J., Zhao, G.-P., Wang, D., & Yao, Y.-F. (2026). Infection-driven epigenetics modulate macrophage innate immunity through the H2BK16ac-ID3-ZBP1 axis. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06432-6

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06432-6

Keywords: macrophage, innate immunity, epigenetics, histone acetylation, H2BK16ac, ID3, ZBP1, Salmonella, HDAC1, HDAC3, E2A, MS-275

The technical centerpiece of the work is a family of fluorescent biosensors called iNap, which fluoresce in proportion to NADPH concentration and can be targeted to specific cellular compartments. When the researchers expressed these sensors in adult mouse cardiomyocytes, they observed that swimming and running exercise elevated the NADPH signal in the cytosol while leaving the mitochondrial pool untouched. This compartmental specificity matters, because cytosolic and mitochondrial NADPH fluxes are known to be independently regulated, and it points the finger away from mitochondrial transhydrogenase and toward cytosolic sources. Among those sources, the pentose phosphate pathway, or PPP, stood out: a glucose-shunting branch of metabolism whose rate-limiting enzyme, glucose-6-phosphate dehydrogenase (G6PD), strips electrons from glucose-6-phosphate and deposits them onto NADP+ to make NADPH.

The causal chain was established through a series of loss-of-function experiments. When the team inhibited PPP activity or depleted cytosolic NADPH in mice, the heart’s response to exercise was blunted: the characteristic enlargement of cardiomyocytes that normally accompanies training failed to materialize. Conversely, the study showed that NADPH itself is a driver of cardiomyocyte growth, acting by inhibiting the HDAC3/C/EBPβ pathway—a signaling axis previously implicated in the control of exercise-induced cardiac growth. In other words, the reducing equivalents manufactured by the PPP do more than keep reactive oxygen species in check; they directly tune an epigenetic and transcriptional program that tells heart cells to grow in a coordinated, physiological manner rather than in the maladaptive fashion seen in disease.

The protective side of the story emerged from mouse models of acute ischemia–reperfusion injury, a scenario that unfolds in millions of patients each year when a blocked coronary artery is reopened and the sudden return of oxygen floods the tissue with reactive oxygen species. Mice with an exercise-activated PPP/NADPH pathway suffered measurably less injury from a subsequent ischemia–reperfusion challenge, and this protection persisted: four weeks after the insult, heart function remained significantly preserved compared with sedentary controls. The mechanism appears to be twofold. First, abundant NADPH sustains the glutathione and thioredoxin antioxidant systems that neutralize the oxidative burst of reperfusion. Second, by suppressing HDAC3 activity, NADPH restrains the transcriptional changes that push stressed cardiomyocytes toward death and maladaptive remodeling.

What makes the study more than an elegant piece of mechanistic cardiology is its drug-discovery angle. The researchers screened 310 Tibetan medicinal compounds for the ability to raise intracellular NADPH, and one molecule rose to the top: lyciumspermidine-0527, a spermidine derivative derived from a plant used in traditional Tibetan medicine. Biochemical and structural analyses showed that this compound directly activates G6PD, the rate-limiting enzyme of the pentose phosphate pathway, stabilizing the enzyme’s active dimeric form. In cultured cardiomyocytes and in living mice, lyciumspermidine-0527 elevated cytosolic NADPH, promoted cardiomyocyte growth, and—most strikingly—alleviated ischemia–reperfusion injury to a degree that rivaled exercise itself.

Safety data accompanying the compound were encouraging. Across a range of doses in vitro and in vivo, lyciumspermidine-0527 did not significantly induce cell death in the heart, and histological examination of heart, liver, lung, kidney, and brain tissue showed no overt toxicity. The compound also maintained redox homeostasis in cardiomyocytes, consistent with its proposed mechanism of boosting, rather than overwhelming, the cell’s antioxidant buffering capacity. Genetic confirmation followed: when G6PD was knocked down, the protective effects of the compound vanished, placing G6PD squarely upstream of the observed benefit and ruling out major off-target explanations for the phenotype.

Conceptually, the findings reframe physiological cardiac hypertrophy as a metabolic checkpoint phenomenon. The healthy heart’s enlargement in response to exercise has long been distinguished from the pathological hypertrophy of hypertension or heart failure by its reversibility and preserved function, but the molecular gatekeepers separating the two states have been only partially mapped. By demonstrating that PPP-derived NADPH is required for exercise-induced growth and simultaneously protective against injury, the study positions a single metabolite as a checkpoint that integrates the demand for biosynthesis (NADPH feeds fatty acid and nucleotide production), antioxidant defense (NADPH powers glutathione reductase), and epigenetic regulation (NADPH inhibits the HDAC3–Ncor complex). Exercise, in this view, is a metabolic intervention, and its cardiac benefits can be recapitulated—at least in mice—by pharmacologically opening a single metabolic valve.

The translational horizon is tantalizing but cautious. Lyciumspermidine-0527 is not yet a drug, and the leap from mouse models of surgically induced ischemia–reperfusion to human myocardial infarction is considerable. G6PD activity is a double-edged sword: the same pathway that supports antioxidant defense in cardiomyocytes also supports nucleotide synthesis and growth in cancer cells, raising questions about systemic effects that would need careful evaluation in longer-term studies. Nonetheless, the identification of a small molecule that directly activates G6PD offers a starting point for medicinal chemistry, and the iNap biosensor toolkit the team deployed provides a template for screening compounds by their ability to raise NADPH in specific subcellular compartments rather than by crude proxies.

For now, the study’s most immediate contribution is conceptual clarity. It explains, in mechanistic terms, why the exercising heart grows well and withstands injury better, connecting the dots from a transcription factor (SP1-driven G6PD expression), through a metabolic flux (the pentose phosphate pathway), to a redox cofactor (cytosolic NADPH), and finally to an epigenetic effector (HDAC3/C/EBPβ) and a clinical phenotype (preserved function after reperfusion). It also validates a natural-product-inspired approach to finding exercise mimetics for the heart. If the PPP/NADPH axis holds up in larger preclinical models, the prospect of a pill that trains the heart’s metabolism—conferring some of exercise’s cardioprotection on patients who cannot exercise—moves from metaphor to plausible pipeline.

Subject of Research: Pentose phosphate pathway-derived NADPH as a metabolic checkpoint regulating exercise-induced physiological cardiac hypertrophy and protection against ischemia–reperfusion injury

Article Title: Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia–reperfusion injury in the heart

Article References: Wu, D., Chen, T., Dong, X., Li, H., Cheng, Z., Li, H., Chao, Y., Li, F., Yin, Y., Guo, F., Xu, X., Zhang, Y., Ning, K., Fu, X., Bian, Y., Ma, F., Ritterhoff, J., Wang, W., & Hu, Q. (2026). Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia–reperfusion injury in the heart. Nature Metabolism. https://doi.org/10.1038/s42255-026-01587-9

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01587-9

Keywords: NADPH, pentose phosphate pathway, cardiac hypertrophy, exercise, ischemia-reperfusion injury, glucose-6-phosphate dehydrogenase, cardiomyocytes, HDAC3, lyciumspermidine-0527, redox homeostasis, cardiac metabolism, Nature Metabolism

Nuclear receptors are ligand-activated transcription factors that bind specific DNA sequences and switch target genes on or off in response to small molecules. Several members of this superfamily are central players in bile acid biology. The farnesoid X receptor, or FXR, is the canonical bile acid sensor, activated by chenodeoxycholic acid and related species, and it feeds back to suppress the enzyme CYP7A1, the rate-limiting step in classical bile acid synthesis, largely through induction of the repressive nuclear receptor SHP. The pregnane X receptor and the constitutive androstane receptor act as xenobiotic and bile acid sensors that induce detoxification and export pathways, protecting hepatocytes from bile acid overload. The liver X receptor links oxysterol sensing to bile acid synthesis via CYP7A1 induction, while the retinoid X receptor serves as a common dimerization partner for many of these receptors. Each of these receptors, however, does not act alone: their output depends on the coregulatory proteins they recruit to DNA.

This is where SMRT enters the picture. SMRT, short for silencing mediator of retinoid and thyroid hormone receptors and also known as NCOR2, is one of the two major corepressors of the nuclear receptor superfamily, the other being its paralog NCoR1. In the absence of activating ligand, many nuclear receptors bind SMRT, which in turn recruits large multiprotein complexes containing histone deacetylases such as HDAC3, along with transducin beta-like proteins and other chromatin-modifying enzymes. These complexes deacetylate histones and maintain local chromatin in a transcriptionally repressive state. When ligand binds, the receptor undergoes a conformational change, releases the corepressor, and recruits coactivators instead. This ligand-dependent corepressor exchange is the fundamental switch that converts receptor binding into transcriptional activation, and it means that the abundance, localization, and post-translational modification state of SMRT directly shapes how strongly and how quickly target genes respond to their ligands.

For bile acid homeostasis specifically, SMRT has been implicated in the regulation of nearly every major nuclear receptor pathway in the hepatocyte and the enterocyte. In the FXR pathway, corepressor exchange at FXR target promoters such as SHP, BSEP, and the intestinal FGF15/FGF19 locus determines the strength of the enterohepatic feedback signal that restrains CYP7A1 expression. In the CAR and PXR pathways, SMRT occupancy at promoters of detoxification genes such as CYP2B and CYP3A, and at bile acid exporters, governs the inducible defense against cholestatic injury. In the LXR pathway, corepressor association with LXR/RXR heterodimers at the CYP7A1 promoter influences the balance between bile acid synthesis and cholesterol efflux. The review emphasizes that these are not independent circuits but an integrated network in which SMRT acts as a shared rheostat, tuning gene expression across pathways in response to nutritional state, circadian cues, and inflammatory signals.

The physiological consequences of disrupting this corepressor function are substantial. Animal studies over the past two decades have shown that perturbing corepressor complexes, particularly the SMRT- and NCoR-associated HDAC3 complex, produces profound metabolic phenotypes. Liver-specific deletion of HDAC3 in mice leads to marked alterations in lipid and bile acid metabolism, reflecting the loss of repressive chromatin marks at metabolic gene promoters. Similarly, mice with impaired corepressor recruitment to specific nuclear receptors display altered bile acid pool sizes, changes in the hydrophobicity of the bile acid pool, and altered sensitivity to cholestatic liver injury. Because bile acids themselves are cytotoxic at high concentrations and pro-carcinogenic when they accumulate in the intestine, the fidelity of this corepressor-mediated feedback is a matter of liver and gut health, not merely transcriptional housekeeping.

The review also highlights the emerging role of SMRT in the enterohepatic circulation itself. Bile acids are secreted into bile, stored in the gallbladder, released into the duodenum after meals, reabsorbed in the terminal ileum, and returned to the liver through portal blood. At each step, nuclear receptors in enterocytes and hepatocytes sense the local bile acid concentration and adjust transporter expression accordingly. SMRT-dependent repression and derepression at these transporter genes, including ASBT in the ileum and NTCP and BSEP in the liver, helps set the flux rate of the entire circulation. Disruption of this tuning can shift the bile acid pool toward more hydrophobic species, which are stronger FXR agonists but also more damaging to membranes, thereby creating a feedback loop that links corepressor function to both signaling intensity and cytotoxic risk.

Beyond classical bile acid metabolism, the review connects SMRT-regulated nuclear receptor signaling to systemic metabolic disease. Bile acids activate FXR and the membrane receptor TGR5 to influence glucose homeostasis, insulin sensitivity, thermogenesis in brown adipose tissue, and energy expenditure. The bile acid pool is also a major determinant of gut microbiome composition, and the microbiome in turn modifies bile acids through deconjugation and dehydroxylation, generating secondary bile acids with distinct receptor specificities. Because SMRT shapes the expression of the enzymes and transporters that determine which bile acids circulate and in what amounts, corepressor function sits upstream of this entire host-microbe metabolic axis. The authors argue that this positions SMRT as a potential node at which diet, microbiome, and nuclear receptor pharmacology converge, with implications for nonalcoholic fatty liver disease, cholestasis, metabolic syndrome, and gastrointestinal cancers.

Therapeutically, the framework has clear implications. FXR agonists such as obeticholic acid are already approved for certain cholestatic conditions and are being evaluated for metabolic liver disease, while dual and selective modulators of FXR, TGR5 agonists, and CAR activators are in various stages of development. The review suggests that the efficacy of such ligands depends not only on receptor binding but on the corepressor and coactivator landscape of the target tissue. A ligand that promotes efficient corepressor release will produce a stronger transcriptional response than one that does not, and tissue-specific differences in SMRT abundance could explain variable drug responses between patients and between liver and intestine. This perspective points toward a second generation of nuclear receptor therapeutics designed with coregulator exchange in mind, and toward biomarkers based on coregulator occupancy that could predict which patients will benefit from bile acid-directed therapies.

The review closes by identifying open questions that will define the next phase of the field. These include mapping the genome-wide occupancy of SMRT at bile acid-related loci in a cell-type-specific manner, determining how post-translational modifications of SMRT such as phosphorylation, ubiquitination, and sumoylation respond to nutritional and inflammatory signals, and clarifying how SMRT and NCoR1 divide labor between hepatocytes, cholangiocytes, and intestinal epithelial cells. Single-cell and chromatin profiling technologies are expected to accelerate this work, as are degrader and PROTAC approaches that can selectively manipulate corepressor complexes. What is already clear, the authors contend, is that bile acid homeostasis cannot be understood as a simple ligand-receptor-feedback circuit. It is a coregulator-dependent system in which SMRT provides the repressive counterweight that gives nuclear receptor signaling its dynamic range, its tissue specificity, and its resilience against metabolic and toxicological stress.

Subject of Research: SMRT corepressor regulation of nuclear receptor signaling in bile acid homeostasis

Article Title: SMRT regulation of nuclear receptors orchestrates bile acid homeostasis

Article References: Kim, K., Fang, S., Hong, S.-H., Cho, H., Leblanc, M., Jacinto, S., Schnabl, B., Atkins, A. R., Yu, R. T., Liddle, C., Truitt, M. L., Fan, W., Lee, C. M., Downes, M., & Evans, R. M. (2026). SMRT regulation of nuclear receptors orchestrates bile acid homeostasis. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01823-y

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01823-y

Keywords: SMRT, NCOR2, nuclear receptors, bile acids, FXR, CYP7A1, cholestasis, HDAC3, liver metabolism, enterohepatic circulation, corepressors, metabolic disease