The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) continues to increase worldwide, partly because of rising rates of obesity and metabolic syndrome. However, a substantial proportion of patients with MAFLD are neither overweight nor obese and are classified as having lean MAFLD. The increasingly recognized phenotype of lean MAFLD challenges the traditional paradigm linking obesity to metabolic risk. Despite a normal body mass index (BMI), lean MAFLD is associated with substantial metabolic dysfunction and a range of extrahepatic manifestations. Evidence from systematic reviews and meta-analyses including more than 10 million individuals indicates that patients with lean MAFLD have metabolic profiles comparable to those of overweight or obese patients with MAFLD, including insulin resistance, dyslipidemia, and hypertension. Importantly, although cardiovascular and cancer-related mortality appear broadly similar across BMI categories, liver-related mortality is consistently higher in lean individuals, suggesting distinct hepatocentric vulnerability. Variation in all-cause mortality estimates is influenced by disease severity, study design, and ethnicity. Important mechanistic factors include genetic susceptibility, sarcopenia, and visceral adiposity. These findings support comprehensive metabolic and hepatic assessment in lean MAFLD beyond BMI-based risk classification. This review examines lean MAFLD as a hepatocentric phenotype with systemic effects beyond BMI.

Hepatocellular carcinoma (HCC) exhibits profound metabolic reprogramming, with enhanced aerobic glycolysis and excess lactate production as defining features. Lactate, once regarded simply as a metabolic byproduct, is now recognized as a powerful epigenetic driver through lysine lactylation, while tumor cells co-opt autophagy to endure metabolic stress. Although traditionally investigated as separate hallmarks of cancer, growing evidence points to their functional intersection. Here, we propose the concept of a coordinated “lactylation-autophagy axis” and clarify its role in remodeling the tumor immune microenvironment. Within this integrated metabolic-epigenetic-proteostatic network, lactate-induced histone lactylation, such as H3K18la, exerts transcriptional control over tumor-associated macrophages, shifting them toward an immunosuppressive M2-like state. Excess extracellular lactate and robust autophagic adaptation cooperate to impair the effector functions of CD8+ T cells and natural killer cells, while providing regulatory T cells with metabolic advantages. We further explore the bidirectional crosstalk within this axis: lactate modulates autophagic flux, potentially through mTOR signaling and non-histone lactylation of autophagy-related proteins (e.g., VPS34, TFEB), whereas autophagy in turn regulates intracellular metabolite pools and lactylation substrates. Notably, several nodes, particularly non-histone lactylation of VPS34, TFEB, and mTOR (K921), have been demonstrated mainly in non-HCC systems; we therefore grade each mechanism as confirmed in HCC, extrapolated from other systems, or hypothetical. This proposed self-reinforcing axis may sustain tumor plasticity, contribute to immune evasion and immunotherapy resistance, and we discuss rational combinatorial strategies—combined targeting of lactate metabolism, lactylation machinery, and autophagic pathways—to sensitize advanced HCC to immune checkpoint blockade.

Metabolic dysfunction–associated steatotic liver disease (MASLD) and alcohol–associated liver disease (ALD) are leading causes of chronic liver injury with overlapping clinical and histological presentations. This study evaluated a composite histologic pattern, termed the Alcohol Liver Pathology Signature (ALPS), for potential use in the differential diagnosis of ALD and MASLD and to explore potential clinical and demographic correlates.

In this retrospective diagnostic-accuracy study, we reviewed 292 liver biopsies performed between 2021 and 2023. ALPS comprised five histologic features: ductular reaction, bile stasis, neutrophilic satellitosis, portal inflammation, and advanced fibrosis (stage 3–4). Cases were categorized as absent (0–1 features), partial (2–3 features), or full (4–5 features). ALPS performance was then further evaluated in an independent temporal validation cohort of de-identified, mixed, and blindly reviewed liver biopsies collected between 2024 and 2025.

MASLD was the most common diagnosis (25.3%), whereas ALD accounted for 4.8%. Full ALPS was present in 92.8% of clinically diagnosed ALD cases. In MASLD, individual ALPS features were common, but only 20.3% showed full ALPS, corresponding to 79.7% specificity for distinguishing clinically diagnosed ALD from MASLD. The independent temporal validation cohort showed findings consistent with those of the original cohort. Finally, within MASLD, full ALPS was more frequent in African American than non-African American patients (29.2% vs. 3.8%).

ALPS may serve as a histologic prompt for further assessment of potential alcohol exposure but should not be considered etiologically specific. Prospective validation incorporating objective measures of alcohol exposure is warranted.

The huge burden of type 1 diabetes mellitus (T1DM) has been a source of concern globally since the Industrial Revolution in the 18th–19th centuries. To this end, studies have shown that certain environmental changes that accompanied the Revolution may have increased the risk and burden of the disease in genetically predisposed individuals. However, documented studies that synthesize these environmental triggers are scarce. As a result, the current study was conceived to synthesize the environmental triggers of T1DM to boost public awareness. Relevant information was retrieved from reputable academic databases; namely, Scopus, PubMed, SpringerLink, and Embase. The results showed that chemical exposure, viral infection, gut microbiome disruption, vitamin and mineral deficiencies, inadequate or exclusive breastfeeding, as well as early exposure to infant feeding formulas could increase the risk and burden of T1DM in genetically predisposed individuals. As a consequence, these triggers could compromise the expression of certain genes involved in insulin synthesis and immune function, such as the human leukocyte antigen (HLA), insulin (INS), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes. This would result in a dysfunctional immune system in which immune cells, such as T-cells and B-cells and molecules, such as cytokines would attack self-tissues, thus causing autoimmunity of the pancreatic beta cells. Environmental triggers could also induce the T1DM pathophysiology by modifying the epigenome of the mentioned genes. Furthermore, some epigenetic changes could be reversed, which would infer that treatment procedures that would include the pathophysiology of the environmental triggers could be more effective.

Emerging evidence suggests that RNA-binding motif (RBM) proteins are involved in hepatocarcinogenesis and act either as oncogenes or tumor suppressors. The objective of this study was to investigate the role of RBM34, an RBM protein, in hepatocellular carcinoma (HCC).

We first examined the expression of RBM34 across cancers. The correlation of RBM34 with clinicopathological features and the prognostic value of RBM34 for HCC was then investigated. Functional enrichment analysis of RBM34-related differentially expressed genes (DEGs) was performed to explore its biological function. RNA sequencing (RNA-seq) was applied to identify downstream genes and pathways affected upon RBM34 knockout. The correlation of RBM34 with immune characteristics was also analyzed. The oncogenic function of RBM34 was examined in in vitro and in vivo experiments.

RBM34 was highly expressed in hepatocellular carcinoma and correlated with poor clinicopathological features and prognosis. RBM34 was positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. A positive correlation was also observed between RBM34, T cell exhaustion, and regulatory T cell marker genes. Knockout of RBM34 significantly inhibited cell proliferation, migration, and xenograft tumor growth, and sensitized HCC cells to sorafenib treatment. RBM34 inhibition reduced FGFR2 expression and affected PI3K-AKT pathway activation in HCC cells.

Our study suggests that RBM34 may serve as a new prognostic marker and therapeutic target of HCC.

Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.

The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.

Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl4)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.

Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.