The pathway, identified by the research team as the KAT2/HDACIIa–PGK–ALDO axis, links chromatin-associated enzyme regulation with the stability and activity of two central glycolytic proteins: phosphoglycerate kinase, or PGK, and aldolase, or ALDO. Glycolysis converts glucose into pyruvate while generating ATP, allowing cells to produce energy rapidly even when mitochondrial respiration is restricted. This flexibility is especially important in intertidal organisms, which can experience abrupt shifts in temperature, oxygen availability, and immersion. It is also a defining feature of many tumors, whose poorly organized blood vessels create regions of hypoxia and metabolic stress.

According to the study, energy stress changes the balance between the acetyltransferase KAT2 and the deacetylase HDACIIa. This shift promotes acetylation of PGK, a chemical modification that affects the protein’s behavior and fate inside the cell. The researchers found that acetylated PGK becomes less vulnerable to ubiquitin–proteasomal degradation, the principal cellular pathway for dismantling damaged or unwanted proteins. By escaping this disposal system, PGK accumulates and forms a stronger functional association with ALDO. The result is not merely an increase in the amount of glycolytic machinery available to the cell, but a coordinated reorganization that gives the pathway greater catalytic capacity under adverse conditions.

The investigators further showed that PGK performs an unexpected function beyond its established role in glycolysis. In its stabilized state, PGK acts as a non-canonical protein kinase, transferring a phosphate group directly to ALDO. This phosphorylation event enhances ALDO’s catalytic efficiency, allowing it to process glycolytic intermediates more effectively. At the same time, phosphorylation protects ALDO from chaperone-mediated autophagy, or CMA, a selective lysosomal degradation pathway that normally recognizes and removes specific proteins. PGK therefore helps preserve ALDO through a second, mechanistically distinct route. The axis simultaneously suppresses proteasomal degradation of PGK and CMA-mediated degradation of ALDO, producing what the researchers describe as a dual degradation-inhibition cascade.

This two-layered stabilization system gives cells a powerful way to amplify glycolytic flux during energy crises. Rather than simply increasing glucose uptake or transcriptionally producing more metabolic enzymes, the pathway extends the lifespan of existing proteins and activates them through post-translational modification. Such regulation can act rapidly, which may be critical when environmental conditions deteriorate faster than a cell can alter gene expression. The mechanism also illustrates how protein degradation systems, often viewed primarily as quality-control networks, can become central regulators of metabolism. By selectively slowing the removal of PGK and ALDO, the cell preserves a functional energy-producing module precisely when ATP demand is high and alternative sources are limited.

The evolutionary comparison began with the biology of sessile oysters living in the intertidal zone. Unlike mobile animals, these shellfish cannot flee when exposed to intense sunlight, rising temperatures, air, or oxygen-poor conditions. Their tissues must repeatedly switch between aerobic respiration and glycolysis while maintaining cellular integrity during cycles of environmental stress. The researchers’ multi-omics analyses, gene-editing experiments, and biochemical assays indicated that the KAT2/HDACIIa–PGK–ALDO pathway contributes to this metabolic adaptability. The pattern resembles the Warburg effect, in which cancer cells favor aerobic glycolysis even when oxygen is available. In both settings, glycolysis provides a flexible and rapidly accessible source of energy while supporting the production of biosynthetic intermediates needed for growth and repair.

The team then examined whether human lung cancer cells use the same molecular circuitry. Their results indicated that lung adenocarcinoma cells increase expression of KAT2A, the human counterpart of the acetyltransferase component, while reducing HDAC5, a related deacetylase. This imbalance favors persistent hyperacetylation of PGK1 at lysine 75, or PGK1-K75. The modified enzyme is protected from proteasomal destruction and is more capable of engaging the downstream pathway. It also promotes phosphorylation of ALDOA at serine 272, or ALDOA-S272. Together, these modifications strengthen glycolytic activity and help cancer cells continue proliferating in an environment characterized by oxygen limitation, nutrient competition, and fluctuating energy availability.

The findings suggest that this metabolic axis may contribute not only to tumor growth but also to invasion and metastasis. A cancer cell that can maintain glycolytic output while its proteins are shielded from degradation may be better equipped to survive detachment, migration, and colonization of new tissues. The study therefore identifies several possible therapeutic intervention points, including KAT2A-dependent acetylation, HDAC5 regulation, PGK1-K75 modification, ALDOA-S272 phosphorylation, and the interactions linking proteasomal and lysosomal quality-control pathways. Blocking the axis could theoretically weaken the metabolic resilience of tumor cells without directly targeting glycolysis at its most fundamental steps. However, because normal cells may also rely on this stress-response system, future treatments would need to distinguish malignant metabolic reprogramming from essential physiological adaptation.

The researchers emphasize that oysters should not be regarded as simple models of human cancer, but as evolutionary systems that can reveal conserved solutions to cellular stress. “The hypoxia and energy crises endured daily by intertidal oysters remarkably mirror the human tumor microenvironment,” said Dr. Wang Chaogang, the study’s first author. Professor Li Li, the corresponding author, described the work as a bridge between marine evolutionary adaptation and cancer metabolism. By tracing how a metabolic defense system emerged and operates in an organism exposed to repeated environmental extremes, the study offers a new perspective on why tumors are so effective at surviving hostile conditions. It also raises broader questions about how ancient stress-response pathways can be repurposed in disease and whether marine organisms may provide previously overlooked clues for precision oncology.

Subject of Research: Intertidal oyster thermal and energy-stress adaptation; glycolytic regulation; human lung adenocarcinoma metabolism

Article Title: The KAT2/HDACⅡa–PGK–ALDO axis constitutes a dual degradation inhibition cascade links energy stress to glycolytic amplification

News Publication Date: 21-Aug-2026

Web References: https://doi.org/10.1073/pnas.2533429123

References: Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2533429123

Image Credits: IOCAS

Keywords: Lung tumors, thermal tolerance, shellfish, glycolytic pathway, cell metabolism, cellular energy, cell survival, oyster biology, lung adenocarcinoma, PGK1, ALDOA, KAT2A, HDAC5, tumor metabolism

Tiefenbacher, A., Gudenus, M., Valcanover, D. et al. Adipose triglyceride lipase driven lipolysis as a targetable metabolic vulnerability in prostate cancer with intrinsic metabolic inflexibility.
Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03545-4

23 July 2026

Prostate cancer metastasis remains one of the greatest clinical challenges, significantly escalating mortality associated with this common malignancy. While previous research has extensively investigated genetic mutations and signaling pathways driving cancer spread, this study introduces a fresh perspective by linking metabolic regulation and epigenetic modifications to metastatic behavior. RBM14, traditionally recognized for its role in RNA metabolism, has now emerged as a critical mediator stabilizing HK2 mRNA, thereby sustaining elevated glycolytic activity. This metabolic reprogramming provides metastatic cancer cells with a rapid energy supply and biosynthetic precursors essential for invasion and survival in distant tissues.

The molecular architecture of this pathway reveals that RBM14 binds directly to HK2 mRNA, protecting it from degradation. Hexokinase 2 (HK2) is a key enzyme catalyzing the initial step of glycolysis by phosphorylating glucose to glucose-6-phosphate, effectively committing glucose to cellular energy metabolism. Enhanced HK2 expression driven by RBM14 ensures an abundant flux through glycolysis, a hallmark of aggressive cancer metabolism often termed the “Warburg effect”. However, the authors uniquely emphasize that this metabolic shift is not merely a consequence but an active driver of metastatic progression thanks to its downstream effects on chromatin modifications.

Intriguingly, the robust glycolytic activity fueled by RBM14-mediated HK2 stabilization leads to elevated intracellular lactate levels. Lactate, traditionally regarded as a metabolic byproduct, has recently been recognized for its signaling functions and involvement in epigenetic regulation. The study highlights H3K18 lactylation, a histone modification where lactate moieties are appended to lysine 18 on histone H3, as a direct epigenetic mark induced by this metabolic rewiring. This histone lactylation event significantly reprograms gene expression profiles to favor metastatic phenotypes, including enhanced motility, invasiveness, and resistance to apoptosis.

From a biochemical perspective, this research integrates the fields of RNA biology, metabolism, and epigenetics into a comprehensive framework explaining prostate cancer metastasis. The use of advanced RNA immunoprecipitation and next-generation sequencing analyses validated the binding affinity of RBM14 for HK2 transcripts and demonstrated the consequent augmentation in glycolytic gene networks. Furthermore, chromatin immunoprecipitation coupled with mass spectrometry provided compelling evidence for the presence and functional significance of H3K18 lactylation in tumor samples exhibiting high RBM14 expression.

In vitro and in vivo experiments further consolidated the conceptual model, where knockdown of RBM14 led to the destabilization of HK2 mRNA, a marked decrease in glycolysis rates, and subsequent reduction in H3K18 lactylation. This intervention translated into diminished metastatic potential in prostate cancer cell lines and mouse xenograft models, underscoring the therapeutic promise of targeting RBM14 or its downstream metabolic and epigenetic pathways. Notably, the study also explored small molecule inhibitors capable of disrupting the RBM14-HK2 interaction, revealing preliminary efficacy in curtailing metastatic spread.

This body of work not only highlights RBM14 as a molecular linchpin in prostate cancer metastasis but also challenges the traditional compartmentalization of metabolic and epigenetic regulation as independent axes of cancer biology. The interplay elucidated here points to a highly integrated regulatory network, suggesting that cancer cells exploit metabolic intermediates not solely for energy but as epigenetic modulators to tightly control gene expression in favor of malignancy. Moreover, lactylation emerges as a key epigenetic marker with potential diagnostic and prognostic implications within the prostate cancer continuum.

The clinical implications beckon a new era of metabolic and epigenetic targeted therapy. Given the poor prognosis associated with metastatic prostate cancer, strategies inhibiting RBM14-mediated HK2 mRNA stabilization or disrupting lactate-driven histone modifications could provide transformative benefits. Early-phase clinical trials targeting similar metabolic pathways in other cancers lend credence to the translational feasibility of this approach. Future research might focus on pharmacologic agents specifically designed to modulate lactylation or RBM14 activity, potentially revolutionizing treatment paradigms for metastatic prostate cancer.

Beyond prostate cancer, these findings may have broader impact across oncology, as metabolic-epigenetic cross-talk likely underlies metastatic behaviors in diverse tumor types. RBM14’s role as an RNA-binding protein stabilizer could be a general mechanism leveraged by cancer cells to sustain metabolic adaptations critical for dissemination. The identification of lactylation opens avenues for discovering other lactate-dependent epigenetic marks influencing chromatin state and cancer evolution. This work thus provides a conceptual template for exploring metabolic regulation of chromatin in cancer progression.

Scientifically, the revelation of H3K18 lactylation as a pro-metastatic epigenetic modification invites deeper inquiries into the enzymatic machinery responsible for adding and removing these lactyl groups. Decoding the “writers,” “readers,” and “erasers” of histone lactylation will enrich understanding of how metabolic flux integrates with gene regulation and how such mechanisms are exploited in cancer. Additionally, the crosstalk between lactylation and other histone marks, such as acetylation and methylation, may reveal complex layers of epigenetic control fine-tuning cancer cell identity and plasticity.

On a methodological note, this study exemplifies the power of combining multi-omics approaches, including transcriptomics, metabolomics, and epigenomics, to untangle the multidimensional regulatory networks driving cancer aggressiveness. The sophisticated experimental design involving genetic, biochemical, and pharmacological manipulations allowed for a nuanced dissection of cause-and-effect relationships in the RBM14-HK2-lactylation axis. This comprehensive approach sets a new standard for dissecting molecular pathways underpinning metastasis and highlights the importance of interdisciplinary collaboration.

In sum, Liu, Guo, You, and colleagues’ discovery of RBM14’s role in stabilizing HK2 mRNA to activate glycolysis and induce H3K18 histone lactylation unveils a vital metabolic-epigenetic circuit fueling prostate cancer metastasis. This landmark study not only advances fundamental understanding of cancer biology but also identifies promising therapeutic targets to impede the spread of a devastating disease. As the oncology community seeks innovative strategies to combat metastasis, targeting the metabolic-epigenetic interface illuminated here represents a compelling frontier with enormous translational potential.

The emerging paradigm underscored by this research suggests that future oncologic therapies may need to simultaneously address metabolic vulnerabilities and epigenetic dynamics to effectively halt the complex process of metastasis. By illuminating how RBM14 orchestrates glycolysis and epigenetic remodeling through HK2 mRNA stabilization and H3K18 lactylation, the study paves the way for novel biomarkers and combinatorial treatment strategies aiming at metabolic and epigenetic aberrations. This comprehensive insight fosters hope for markedly improved outcomes for patients suffering from advanced prostate cancer.

In conclusion, this study fundamentally reshapes the understanding of how metabolic reprogramming and histone modifications intersect to drive prostate cancer metastasis. The identification of RBM14 as a critical stabilizer of HK2 mRNA and the elucidation of H3K18 lactylation as a pivotal epigenetic modification open profound new vistas for cancer research and therapeutics. As we advance toward precision medicine, integrating metabolic and epigenetic targeting holds the promise of unlocking more effective therapies to arrest cancer progression and improve patient survival.

Subject of Research: Role of RBM14 in prostate cancer metastasis via HK2 mRNA stabilization and activation of glycolysis and epigenetic modification (H3K18 lactylation).

Article Title: RBM14 drives prostate cancer metastasis via stabilizing HK2 mRNA to activate glycolysis and H3K18 lactylation.

Article References: Liu, Z., Guo, H., You, Z. et al. RBM14 drives prostate cancer metastasis via stabilizing HK2 mRNA to activate glycolysis and H3K18 lactylation. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03131-w

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-026-03131-w

Clear cell renal cell carcinoma has long posed a formidable challenge to oncologists due to its aggressive nature and resistance to conventional therapies. Despite advances in targeted treatments and immunotherapies, the molecular intricacies that underpin ccRCC progression remain incompletely understood. This latest research provides critical insights into how metabolic shifts within cancer cells are orchestrated to support unchecked proliferation and survival.

Central to this groundbreaking discovery is FUT8 (fucosyltransferase 8), an enzyme known primarily for its function in adding fucose sugars to glycoproteins—a modification known as core fucosylation. The research team led by Guo, Jiang, Wang, and colleagues has now demonstrated that FUT8’s influence extends far beyond glycosylation. They reveal its unexpected capacity to reprogram glycolytic metabolism, the process by which cancer cells convert glucose into energy and building blocks necessary for growth.

This metabolic reprogramming pivots around PKM2 (pyruvate kinase M2), a key glycolytic enzyme known to play a crucial role in cancer metabolism. Under normal physiological conditions, PKM2 regulates the final step of glycolysis, balancing energy production with anabolic processes. However, the research uncovers that FUT8 promotes an unusual biochemical modification—lactylation—on PKM2, dramatically altering its function and driving tumor cell metabolism towards favoring cancer progression.

Lactylation, a recently discovered post-translational modification, involves the addition of lactate-derived lactyl groups to lysine residues on proteins. While initially characterized in histones affecting gene expression, this study extends the concept by showing lactylation’s impact on metabolic enzymes, unveiling a new layer of regulatory complexity. In ccRCC cells, PKM2 lactylation enhances enzymatic activity and stability, fostering an environment ripe for accelerated glycolysis and tumor growth.

Employing an array of cutting-edge techniques including mass spectrometry, metabolic flux analysis, and in vivo tumor models, the researchers delineated the biochemical pathway by which FUT8 exerts this effect. They observed elevated FUT8 expression in ccRCC patient samples correlating with increased PKM2 lactylation levels, glycolytic gene signatures, and poor clinical prognosis. Functional experiments confirmed that silencing FUT8 diminished PKM2 lactylation, impairing glycolytic flux and slowing tumor progression.

Importantly, the study delineates a feed-forward loop wherein elevated FUT8 expression enhances the metabolic switch toward glycolysis, generating abundant lactate, which in turn facilitates further lactylation of PKM2. This self-reinforcing circuit creates a metabolic state that supports rapid tumor expansion and resistance to metabolic stress. Interrupting this loop offers a tantalizing therapeutic opportunity.

Current ccRCC treatments targeting vascular growth factors or immune checkpoints have limitations, often leading to relapse or resistance. The identification of the FUT8-PKM2-lactylation axis opens new avenues for metabolic intervention. By specifically targeting FUT8 enzymatic activity or interfering with PKM2 lactylation, it might be possible to disrupt cancer’s energy supply line, sensitizing tumors to existing therapies or halting progression.

The study also underscores the increasing significance of metabolic post-translational modifications as critical regulators of cancer biology. Beyond phosphorylation and acetylation, the role of novel modifications such as lactylation is emerging as a key contributor to the metabolic plasticity that characterizes aggressive tumors. These findings pivot future research towards exploring lactylation-centric therapeutic strategies.

Moreover, the researchers highlight that FUT8’s role may not be confined to ccRCC. Given the prevalence of metabolic reprogramming across multiple cancer types, FUT8-mediated lactylation could represent a broader oncogenic mechanism. Future studies are anticipated to investigate the role of this pathway in other malignancies, potentially expanding the clinical impact of these findings.

This research also opens questions about the interplay between tumor metabolism and the tumor microenvironment. Lactate has long been recognized as an immunosuppressive metabolite within the tumor milieu. By driving PKM2 lactylation, FUT8 may indirectly modulate immune evasion strategies, compounding the challenges of anti-cancer immunity. Understanding these interactions could inform combination therapies that address both tumor metabolism and immune modulation.

In conclusion, the discovery of FUT8’s ability to reprogram glycolytic metabolism through PKM2 lactylation unveils a sophisticated mechanism that fuels ccRCC progression. This work not only advances our molecular understanding of kidney cancer but also lays the foundation for the development of innovative metabolic therapies. As metabolic targeting gains traction in oncology, such studies are invaluable for charting new paths towards more effective, durable cancer treatments.

The implications of this research resonate far beyond the laboratory. By illuminating the metabolic underpinnings of ccRCC, this study offers hope for patients battling this aggressive cancer. Future translational efforts aimed at harnessing these insights could ultimately transform the clinical landscape, converting cancer’s metabolic vulnerabilities into therapeutic triumphs.

Subject of Research: The molecular mechanisms by which FUT8 reprograms glycolytic metabolism and promotes PKM2 lactylation to drive the progression of clear cell renal cell carcinoma.

Article Title: FUT8 reprograms glycolytic metabolism to promote PKM2 lactylation and drive clear cell renal cell carcinoma progression.

Article References:
Guo, Z., Jiang, H., Wang, X. et al. FUT8 reprograms glycolytic metabolism to promote PKM2 lactylation and drive clear cell renal cell carcinoma progression. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03013-1

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-026-03013-1