Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related mortality globally, predominantly associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These infections drive persistent liver inflammation, culminating in cellular dysregulation, fibrosis, and cancer. Despite advancements in targeted therapies, drug resistance and the lack of reliable biomarkers for patient stratification still terribly hinder the treatment of viral HCC. To this end, the review delves into the intricate mechanisms underlying the malignant transformation of viral hepatitis to HCC, including viral integration, genomic instability, epigenetic modifications, oxidative stress, gut microbiota dysbiosis, chronic inflammation, immune escape, and abnormal signaling pathways, highlighting their complex interactions and synergies. Cutting‐edge preclinical and clinical advancements in HCC management, including lifestyle modifications, drug therapies, immunotherapies, gene‐based approaches, and innovative treatments, are further investigated, with particular priority given to their therapeutic potential and future applications in overcoming current limitations. By synthesizing recent scientific and clinical insights, this review aims to deepen the understanding of HCC pathogenesis in the context of chronic viral hepatitis, paving the way for novel therapeutic targets and personalized treatment strategies, ultimately improving patient outcomes.

Acute liver failure (ALF) is a severe life-threatening disease associated with the disorder of the gut-liver axis. However, the cellular characteristics of ALF in the gut and related therapeutic targets remain unexplored. Here, we utilized the D-GALN/LPS (D/L)-induced ALF model to characterize 33,216 single-cell transcriptomes and define a mouse ALF intestinal cellular atlas. We found that unique, previously uncharacterized intestinal immune cells, including T cells, B cells, macrophages, and neutrophils, are responsive to ALF, and we identified the transcriptional profiles of these subsets during ALF. We also delineated the heterogeneity of intestinal epithelial cells (IECs) and found that ALF-induced cell cycle arrest in intestinal stem cells and activated specific enterocyte and goblet cell clusters. Notably, the most significantly altered IECs, including enterocytes, intestinal stem cells and goblet cells, had similar activation patterns closely associated with inflammation from intestinal immune activation. Furthermore, our results unveiled a common Ep300-dependent transcriptional program that coordinates IEC activation during ALF, which was confirmed to be universal in different ALF models. Pharmacological inhibition of Ep300 with an inhibitor (SGC-CBP30) inhibited this cell-specific program, confirming that Ep300 is an effective target for alleviating ALF. Mechanistically, Ep300 inhibition restrained inflammation and oxidative stress in the dysregulated cluster of IECs through the P38-JNK pathway and corrected intestinal ecology by regulating intestinal microbial composition and metabolism, thereby protecting IECs and attenuating ALF. These findings confirm that Ep300 is a novel therapeutic target in ALF and pave the way for future pathophysiological studies on ALF.

Melanoma is the most lethal skin cancer with rising incidence worldwide. Despite significant advances in target therapy and immunotherapy, low response rates and the development of drug resistance remain key clinical barriers affecting patient prognosis. The complex interplay between multiple signaling molecules and pathways has brought little understanding of melanoma pathogenesis and resistance. The genetic mutation and hypermetabolic environment of melanoma cells lead to increasing demands for protein synthesis and perturb proteostasis resulting in endoplasmic reticulum (ER) stress. Subsequently, three unfolded protein response (UPR) signaling branches, represented by IRE1α, PERK and ATF6, are activated to direct cell fate towards pro-survival or pro-apoptosis depending on the intensity and duration of ER stress. In this review, we summarize ER stress and UPR in melanoma cells and tumor-infiltrating immune cells along with the crosstalk among these pathways. We provide the latest advances in understanding melanoma pathogenesis and resistance and discuss the potential of targeting the ER stress or UPR process for melanoma therapy.