Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder with a complex pathogenesis. Although epitranscriptomic modifications such as N6-methyladenosine (m6A) have been implicated in NAFLD, the role of N1-methyladenosine (m1A) and its regulators is largely unexplored. Recently, YTHDF1, a well-characterized m6A reader, was also shown to recognize m1A; however, the functional consequences of this dual specificity are unknown. This study aimed to investigate the role of YTHDF1 in NAFLD pathogenesis and to explore whether its function is mediated through recognition of RNA methylation modification on specific target mRNAs.

Expression of YTHDF1 in NAFLD was analyzed in the GEO database. Loss-of-function studies for YTHDF1 were conducted in vivo (high-fat diet-fed mice) and in vitro (free fatty acid-treated HepG2 cells) in models of NAFLD. We employed RNA-seq and m1A-MeRIP-seq to identify key targets, followed by mechanistic validation of the YTHDF1–m1A–NUPR1 axis using biochemical, histological, and mRNA stability assays.

We identified a critical role for YTHDF1 in promoting hepatic steatosis. NUPR1, a stress-induced transcriptional regulator, undergoes m1A modification. YTHDF1 directly binds to m1A-modified NUPR1 mRNA, enhancing its stability, thereby leading to elevated NUPR1 protein levels. Functionally, upregulated NUPR1 acts as a core driver of NAFLD pathogenesis by activating lipogenic and suppressing fatty acid β-oxidation genes, thereby exacerbating hepatic lipid accumulation.

Our study unveils a novel epitranscriptomic mechanism in which YTHDF1, functioning as a dual-specificity reader, governs NAFLD progression through the m1A-NUPR1 axis. This not only expands the understanding of RNA modification recognition but also establishes the YTHDF1–m1A–NUPR1 pathway as a promising therapeutic target for metabolic liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become one of the leading causes of chronic liver diseases in China, imposing a substantial and growing burden on the healthcare system. Considering the large number of individuals affected by MAFLD and the gap in disease management capacity at the primary care level, standardized guidance tailored to primary healthcare settings is urgently needed. In response, the Chronic Disease Management Branch of the China Medical Biotechnology Association convened a multidisciplinary working group incorporating hepatologists, general practitioners, and other specialists to initiate the first China national Guidelines for Diagnosis and Management of Metabolic Dysfunction-associated Fatty Liver Disease in Primary Care (2025). These guidelines provide recommendations and suggestions covering screening, risk assessment, diagnosis, treatment, referral pathways, and follow-up tailored for primary care institutions, thereby improving the long-term outcomes for the population with MAFLD and comprehensively strengthening the role of primary healthcare in chronic liver disease management.

The optimal management strategy for adults with immune-tolerant (IT) chronic hepatitis B infection remains undefined. This study aimed to investigate the efficacy and predictive factors of a pegylated interferon (Peg-IFN)-based treatment strategy in IT patients with chronic HBV infection.

In this pilot, open-label, prospective study, 286 patients aged 18 to 60 years with IT characteristics were enrolled and allocated to one of three groups. The combination group received Peg-IFN for 48–96 weeks, with tenofovir disoproxil fumarate (TDF) initiated at week 12 and continued through week 96 (n = 103). The monotherapy group received TDF monotherapy alone (n = 125), and the control group was monitored without therapeutic intervention (n = 58).

No patients in the control group met any predefined efficacy endpoints. Intention-to-treat analysis showed that patients in the combination group achieved significantly higher virological response rates (71.8% vs. 53.6%, p = 0.005), hepatitis B e antigen seroconversion rates (15.5% vs. 1.6%, p < 0.001), and hepatitis B surface antigen (HBsAg) loss rates (10.7% vs. 0%, p < 0.001) compared with those in the monotherapy group at week 96. In the combination group, the cumulative rate of HBsAg loss was 5.4% at week 48 and increased to 11.8% by week 96. Independent predictors of achieving either hepatitis B e antigen seroconversion or HBsAg loss were baseline age under 30 years (odds ratio = 0.217, 95% confidence interval: 0.048–0.976, p = 0.046) and a decline in HBsAg level greater than 1 log10 IU/mL by week 24 (odds ratio = 13.976, 95% confidence interval: 2.506–77.932, p = 0.003).

A Peg-IFN-based treatment strategy significantly increases response rates compared with TDF monotherapy or observation in patients with IT characteristics.

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.