Hepatocellular carcinoma ranks as the sixth most prevalent malignancy worldwide and is the third leading cause of cancer mortality, posing a significant health burden globally. The increasing incidence of obesity, metabolic syndrome, and type 2 diabetes has catalyzed a surge in fatty liver disease, which in turn escalates the risk for HCC. Epidemiological data underscore a harrowing statistic: approximately 3% of patients with fatty liver disease per annum progress to liver cancer, with the Asian continent disproportionately affected, encompassing nearly one-quarter of the population. Despite advancements in immunotherapies, including immune checkpoint inhibitors, therapeutic responses in fatty liver-associated HCC remain suboptimal, warranting urgent investigation into novel therapeutic avenues.

To interrogate the pathological crosstalk fueling this malignancy, the HKUMed team developed an innovative murine model that faithfully replicates human MAFLD and its oncogenic progression. Employing high-resolution single-cell RNA sequencing, they profiled an extensive array of liver-resident and tumor-infiltrating cells across different disease stages. This approach enabled an unprecedented dissection of the transcriptomic dynamics and intercellular signaling between hepatocytes, hepatic stellate cells, and various immune populations within the liver milieu, revealing novel oncogenic circuits.

A central discovery was the identification of the Midkine (MDK) signaling axis as a crucial oncogenic driver in fatty liver-related hepatocarcinogenesis. MDK, a heparin-binding growth factor, was found to be secreted by hepatic cells and to engage its receptor LRP1 on neighboring cells, potentiating tumorigenic processes. Elevated MDK expression correlated strongly with diminished patient outcomes, characterized by increased tumor recurrence rates and reduced relapse-free survival in non-viral, non-alcoholic etiologies of liver cancer. This discovery sheds light on a previously underappreciated molecular pathway contributing to the immune evasion and tumor promotion in MAFLD-associated HCC.

Mechanistically, the study revealed that MDK disrupts immune homeostasis within the tumor microenvironment by skewing macrophage polarization from a tumor-suppressive phenotype towards one that fosters tumor growth. The deleterious impact extends to T lymphocytes, which undergo progressive dysfunction—termed T-cell exhaustion—characterized by diminished cytotoxic capacity and aberrant self-reactivity. This immunosuppressive milieu facilitates unchecked tumor proliferation and circumvents the host’s immune surveillance mechanisms, unveiling an intricate immune escape strategy exploited by fatty liver-driven cancers.

Intriguingly, intervention with Resmetirom markedly attenuated these malignant processes in preclinical models. Beyond its known role in reducing hepatic lipid accumulation and fibrosis, Resmetirom treatment led to a substantial downregulation of MDK expression. This suppression mitigates the oncogenic signaling cascade, thereby inhibiting tumor growth. Moreover, the combination of Resmetirom with MDK pathway inhibitors produced a synergistic anticancer effect, intensifying improvements in metabolic parameters, enhancing immune cell function, and suppressing tumor development. These synergistic effects underscore the therapeutic viability of targeting both metabolic dysfunction and oncogenic signaling simultaneously.

Resmetirom’s multifaceted mechanisms also extend to modulating the tumor microenvironment, transforming it from immunosuppressive to immunostimulatory. By recalibrating macrophage phenotypes and rescuing exhausted T cells, the drug reinstates anti-tumor immunity. This paradigm shift holds profound implications for clinical management, signifying the potential to overcome the current limitations of immunotherapies in fatty liver-associated HCC. Consequently, Resmetirom could serve not only as a metabolic agent but also as an adjunct to enhance immunotherapeutic efficacy in liver cancer.

Professor Irene Ng Oi-lin, the study’s senior author, emphasized the significance of this discovery in reframing the pathogenesis of MAFLD-related liver cancer. “Our findings delineate that fatty liver-associated hepatocellular carcinoma is driven not merely by excess lipid accumulation but by a pivotal cancer-promoting pathway orchestrated by MDK and its receptor. Therapeutically targeting this axis can reprogram the immune landscape and impede tumor progression,” she remarked. This insight paves the way for precision-based, mechanism-targeted therapies.

Looking ahead, the research team is poised to validate novel biomarkers linked to the MDK pathway in larger patient cohorts, facilitating patient stratification and personalized medicine approaches. Their proposed trajectory involves clinical trials combining Resmetirom with immunotherapeutic and targeted agents to establish an innovative, prevention-focused treatment model for high-risk MAFLD patients. Such a model aims to intervene before malignant transformation, thereby reducing the incidence and burden of liver cancer.

The implications of this research extend beyond clinical applications, offering a conceptual leap in understanding the interplay between metabolic dysfunction, oncogenesis, and immune regulation in the liver. By harnessing advanced single-cell analytics and sophisticated animal models, the study exemplifies how integrating metabolic and immune-targeted therapeutics can revolutionize cancer treatment paradigms, particularly in metabolic disease-driven malignancies.

This transformative work stands as a testament to HKUMed’s commitment to pioneering biomedical research and exemplifies the power of interdisciplinary collaboration. The study was co-led by Professor Irene Ng Oi-lin and Professor Daniel Ho Wai-Hung, with key contributions from early-career researchers including Dr. Vanilla Zhang Xin and PhD candidate Tina Suoangbaji, reflecting a vibrant research ecosystem fostering innovation and translational impact.

As MAFLD and related metabolic disorders continue to escalate globally, with concomitant rises in liver cancer incidence, these findings offer a beacon of hope. Resmetirom emerges as a frontrunner in the therapeutic arsenal, not only to modulate metabolic derangements but to serve as a lynchpin in cancer prevention strategies. The ongoing efforts to translate these findings into clinical practice may herald a new era in liver disease management, profoundly altering the landscape of hepatology and oncology.

Subject of Research:
Article Title: Repurposing Resmetirom suppresses MASH-associated hepatocellular carcinoma, with mechanistic implications of MDK/LRP1-mediated metabolic reprogramming and immunosuppression
News Publication Date: 12-Jan-2026
Web References: DOI: 10.1097/HEP.0000000000001675
Image Credits: HKU
Keywords: Macrophages, Hepatocellular carcinoma, Metabolic dysfunction-associated fatty liver disease, Resmetirom, Midkine, Immune suppression, Tumor microenvironment, Single-cell RNA sequencing, Immunotherapy, Liver fibrosis, Tumor immunology

PAK4 inhibitors initially garnered attention through the development of multiple small molecules with varying degrees of potency and selectivity. Notable among these are PF-3758309, a pan-PAK inhibitor, and GNE-2861, a group II-specific PAK inhibitor. Despite their promising preclinical data, such agents faced setbacks when PF-3758309 exhibited unfavorable pharmacokinetics that halted its progress in early clinical trials. Meanwhile, KPT-9274, a dual inhibitor targeting both PAK4 and the nicotinamide phosphoribosyltransferase (NAMPT) enzyme, has progressed into phase I clinical trials against advanced solid tumors and lymphomas, underscoring a persistent interest in modulating PAK4 activity therapeutically even amidst challenges.

The quest for a selective, orally bioavailable PAK4 inhibitor capable of advancing into clinical stages remains critical. Addressing these gaps, the novel compound ND201651 emerges as a highly selective PAK4 inhibitor with favorable pharmacokinetic properties, warranting extensive evaluation in metabolic disorder models. Intriguingly, ND201651 has demonstrated profound efficacy in mouse models of obesity and metabolic syndrome, manifesting in significant weight loss that occurs independently of altered feeding or locomotor behavior. This decouples the metabolic benefits from changes in energy intake or expenditure, suggesting a direct mechanistic impact on metabolic pathways regulated by PAK4.

Pathophysiologically, ND201651 attenuates adipocyte hypertrophy and inflammatory macrophage infiltration within adipose tissue, crucial hallmarks of metabolic dysfunction. These anti-inflammatory and remodeling effects in adipose depots pave the way for enhanced systemic insulin sensitivity, as reflected in improved glucose tolerance tests. Further molecular analyses reveal upregulation of genes essential for fatty acid β-oxidation such as Cpt1a, Acox1, and Hmgcs2 following ND201651 administration, aligning with reduced hepatic lipid accumulation under dietary stress induced by both high-fat and ketogenic regimens. These findings position PAK4 inhibition as a multifaceted strategy directly remodeling metabolic tissue environments at the cellular and transcriptional levels.

Skeletal muscle, a major site of glucose disposal, also benefits significantly from PAK4 inhibition. ND201651 enhances glucose tolerance through an AMPK-dependent mechanism, promoting GLUT4 translocation to the plasma membrane and thus facilitating glucose uptake. Strikingly, such metabolic gains were absent in genetically engineered Pak4 knockout mice, confirming the specificity of ND201651’s pharmacological target engagement. This specificity differentiates ND201651 from less selective kinase inhibitors, highlighting the importance of precision targeting in therapeutic design to mitigate off-target effects and optimize metabolic outcomes.

Anticipating translational applications, the therapeutic potential of PAK4 extends beyond inhibition to targeted protein degradation strategies. Proteolysis targeting chimera (PROTAC) technology, which engenders selective degradation of target proteins, has been adapted effectively for PAK4. The first generation of peptide-based PAK4 PROTACs manifested robust anti-tumor efficacy in renal carcinoma models following intermittent intraperitoneal administration. Subsequently, second-generation PAK4-targeting PROTACs have demonstrated notable suppression of lung tumor metastases with systemic intravenous dosing, underscoring the therapeutic versatility of proteolytic strategies.

Capitalizing on these advancements, the PAK4-selective PROTAC SJ-05 has been developed as an oral agent derived from the ND201651 chemical scaffold. SJ-05 preserves the selectivity and bioavailability of its precursor while effectively degrading PAK4 protein upon oral administration in murine models. Notably, a ten-day oral regimen of SJ-05 in a sarcopenia mouse model successfully mitigated muscle atrophy, a metabolic complication with significant clinical burden. These data substantiate the concept that pharmacologically induced PAK4 degradation may provide superior or complementary benefits compared to traditional kinase inhibition, possibly due to sustained suppression of PAK4 signaling outputs.

While these therapeutic candidates mark significant milestones, several challenges remain on the path toward clinical translation. Crucially, the selectivity of inhibitors and degraders against closely related kinase family members such as PAK1 must be optimized to minimize unintended effects. Long-term safety profiles require thorough elucidation, particularly given the essential roles of PAK4 in normal cellular homeostasis. Comparative studies evaluating the efficacy and safety of kinase inhibition versus targeted degradation will be vital in defining optimal therapeutic modalities for PAK4-driven diseases.

Moreover, given the broad implications of PAK4 in diverse metabolic tissues—including liver, adipose, and muscle—future investigations should explore the systemic metabolic consequences of chronic PAK4 modulation. This holistic perspective is essential for addressing complex metabolic disorders characterized by multi-organ dysfunction. As these efforts advance, integration with existing therapies for obesity, diabetes, and fatty liver disease will be imperative to delineate the unique and additive benefits of PAK4-targeted strategies within current clinical paradigms.

In summary, the evolving landscape of PAK4 therapeutics is transforming from early pan-kinase inhibition attempts toward highly selective, orally bioavailable inhibitors and innovative PROTAC-based degraders. These breakthroughs promise to reshape therapeutic approaches to both cancer and metabolic diseases, integrating molecular precision with systemic metabolic correction. As the field moves forward, interdisciplinary research combining medicinal chemistry, metabolic biology, and clinical sciences will be paramount in harnessing the full potential of PAK4 modulation for patient benefit.

The promising efficacy of ND201651 and SJ-05 underscores the critical role of PAK4 in metabolic regulation and opens new avenues for designing next-generation drugs. Such agents not only confront obesity and insulin resistance mechanistically but also address pathological features such as fatty liver and muscle wasting, thereby offering comprehensive metabolic support. The dual capacity to inhibit enzymatic activity and induce protein degradation expands the therapeutic toolkit, potentially yielding tailored strategies for diverse patient populations and disease contexts.

Ultimately, the pursuit of selective PAK4 targeting aligns with broader trends in precision medicine, where detailed understanding of molecular signaling pathways informs rational drug design. The therapeutic nuances uncovered in recent studies highlight the intricate balancing act between efficacious target suppression and the maintenance of cellular homeostasis. By advancing PAK4 inhibitors and degraders through rigorous preclinical and clinical investigation, the scientific community edges closer to novel, impactful treatments for some of the most challenging metabolic disorders facing global health.

Subject of Research: PAK4’s role in metabolic diseases and its therapeutic targeting through selective inhibition and protein degradation.

Article Title: PAK4 in metabolic diseases: regulation by nutrient signals and therapeutic implications.

Article References:
Bang, I.H., Park, B.H. & Bae, E.J. PAK4 in metabolic diseases: regulation by nutrient signals and therapeutic implications. Exp Mol Med (2026). https://doi.org/10.1038/s12276-026-01645-y

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01645-y

Keywords: PAK4, metabolic disease, kinase inhibitor, PROTAC, obesity, diabetes, fatty liver, AMPK, GLUT4, fatty acid oxidation

The TCA cycle, often referred to as the Krebs cycle or citric acid cycle, is a central metabolic pathway through which cells generate vital energy molecules like ATP. In the context of liver metabolism, efficient TCA cycle functioning is essential not only for energy homeostasis but also for managing lipid accumulation and oxidative stress—two major factors implicated in MASLD pathogenesis. The study’s authors reveal that post-translational modification of IDH1 by crotonylation substantially boosts its enzymatic activity, thereby accelerating the TCA cycle flux and mitigating the metabolic derangements associated with fat-laden hepatocytes.

Crotonylation is a form of histone modification where a crotonyl group is added to lysine residues on proteins. Traditionally studied in the context of epigenetic regulation, crotonylation’s emerging role in regulating metabolic enzymes represents a paradigm shift in how biochemical modifications influence cellular metabolism. The research team demonstrated that crotonylation of IDH1 specifically enhances the enzyme’s ability to catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate, an essential step in the TCA cycle that fuels downstream reactions crucial for cellular energy production.

Mechanistic investigations revealed that crotonylated IDH1 undergoes structural changes that increase substrate affinity and catalytic turnover. This fine-tuning of enzymatic activity facilitates improved mitochondrial function and reduces the accumulation of metabolic intermediates that are otherwise dysregulated in MASLD. By maintaining a more robust mitochondrial metabolic flux, crotonylation indirectly curbs lipotoxicity and reduces the oxidative stress burden on hepatocytes, two interrelated processes that aggravate liver injury in MASLD.

Utilizing advanced proteomic techniques, the researchers quantified crotonylation levels in liver tissues derived from MASLD patients and corresponding animal models. Intriguingly, they observed a significant depletion of crotonylation marks on IDH1 in diseased states, correlating with diminished enzyme activity and perturbed TCA cycle dynamics. This discovery suggests that impaired crotonylation could be a contributing factor to the metabolic dysfunction characterizing MASLD and offers a promising biomarker for disease progression.

To further validate their findings, the team engineered mouse models with liver-specific mutations that either mimic constitutive crotonylation or prevent this modification on IDH1. Mice exhibiting enhanced IDH1 crotonylation were remarkably protected from high-fat diet-induced steatosis and subsequent liver inflammation. These animals showed improved biochemical parameters, decreased lipid accumulation, and reduced histopathological signs of MASLD, underscoring the therapeutic potential of modulating crotonylation pathways.

Beyond the liver-specific effects, this discovery may have broader implications for systemic metabolism. Given that the TCA cycle is a central hub for energy metabolism across tissues, augmenting crotonylation of IDH1 or similar metabolic enzymes could represent a novel strategy for treating metabolic syndromes that extend beyond primary liver disease. The research opens up new vistas for drug development aimed at enhancing endogenous protein modifications rather than directly targeting enzyme active sites, a method that could yield higher specificity with fewer adverse effects.

Underlying these biological insights, the team employed innovative biochemical assays and cutting-edge mass spectrometry to trace crotonylation dynamics in living cells under varying metabolic conditions. They revealed that nutrient status and metabolic stress modulate crotonylation levels, suggesting this modification serves as a responsive regulatory mechanism adapting enzymatic activity to cellular energy demands. Such findings highlight the exquisite control cells exert over metabolic fluxes via reversible protein modifications, reshaping current models of metabolic regulation.

An exciting aspect of the research involves the interplay between crotonylation and other post-translational modifications affecting IDH1, such as acetylation and phosphorylation. The complex crosstalk between these modifications appears to fine-tune IDH1’s function in a context-dependent manner, potentially integrating multiple signaling pathways related to nutrient sensing and stress response. Future work disentangling these interactions could provide a comprehensive framework for understanding metabolic enzyme regulation.

The clinical implications of this work are profound. With MASLD on the rise globally due to increasing prevalence of obesity and type 2 diabetes, the identification of modifiable biochemical pathways offers a fresh avenue for therapeutic intervention. Current drugs targeting lipid metabolism or inflammation have had limited success, but targeting crotonylation pathways might circumvent these obstacles by restoring fundamental energy metabolism. Moreover, this approach has the advantage of enhancing endogenous metabolic capacity rather than imposing exogenous interventions that might disrupt systemic balances.

Furthermore, the study’s insights into mitochondrial function shed light on how metabolic flexibility—that is, the ability of cells to adapt energy production pathways in response to diet and environment—can be manipulated for therapeutic benefit. Mitochondrial dysfunction is a hallmark not only of MASLD but many chronic diseases, including neurodegeneration and cancer. Therefore, crotonylation-modulated IDH1 activity might emerge as a universal target in diverse pathologies involving mitochondrial impairment.

Given these promising outcomes, the study paves the way for clinical exploration of agents capable of modulating protein crotonylation. Small molecules that enhance crotonyl-CoA availability or inhibit de-crotonylases could serve as lead compounds for drug development. These therapeutic strategies would differ fundamentally from enzyme inhibitors or receptor modulators, operating instead by augmenting beneficial protein modifications to restore physiology.

This research also prompts a reevaluation of crotonylation’s role in broader epigenetic and metabolic contexts. Its dual role in regulating chromatin structure and enzymatic activity suggests it may coordinate gene expression with metabolic adaptation—a vital process during cellular stress, differentiation, or disease. Deciphering this coordination will have far-reaching implications for biology and medicine.

In sum, the crotonylation of IDH1 represents a vital metabolic checkpoint controlling the progression of MASLD through enhancement of the TCA cycle. By illuminating this molecular mechanism, Liu et al. offer a groundbreaking perspective that bridges epigenetic modification and metabolic control. Their work not only elucidates a novel biological principle but also carves a path toward innovative therapies for one of the most pressing liver disorders of our time.

Subject of Research:
The biochemical modulation of IDH1 via crotonylation and its impact on Metabolic Associated Steatotic Liver Disease (MASLD) progression through enhancement of the tricarboxylic acid cycle.

Article Title:
Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle.

Article References:
Liu, S., Ji, Y., Wei, L. et al. Crotonylation of IDH1 alleviates MASLD progression by enhancing the TCA cycle. Nat Commun 16, 7961 (2025). https://doi.org/10.1038/s41467-025-62731-9

Image Credits: AI Generated