Hepatocellular carcinoma is characterized by considerable molecular heterogeneity, which complicates prognostic predictions and contributes to therapeutic resistance. This study aimed to develop a molecular classification framework grounded in lipid droplet-associated genes (LDAGs) and to comprehensively elucidate their biological significance and clinical applicability in guiding personalized treatment approaches. By leveraging multi-cohort datasets, we defined LDAG-based molecular subtypes and systematically characterized their genomic alterations, metabolic features, pathway activation patterns, and therapeutic vulnerabilities. Three distinct subtypes (C1–C3) were identified according to LDAG expression patterns, each demonstrating unique clinical outcomes, mutational profiles, and metabolic reprogramming. The C1 subtype correlated with the poorest overall survival, more advanced tumor stages, and activation of pro-proliferative signaling pathways. Therapeutic vulnerabilities were subtype-dependent, with C1 showing heightened sensitivity to sorafenib. Five pivotal LDAGs (PLIN3, SET, CKAP4, RAP1B, and PISD) were implicated in the aggressive phenotype of C1, among which PLIN3 exhibited the strongest prognostic value. Functional assays confirmed that PLIN3 knockdown reduced lipid accumulation, suppressed cell proliferation and migration, and impaired tumorigenesis, whereas its overexpression promoted aggressive tumor behavior. In conclusion, our LDAG-based classification system stratifies hepatocellular carcinoma into three clinically relevant subtypes. PLIN3 emerges as a promising prognostic biomarker and therapeutic target, thereby mechanistically linking lipid metabolism to hepatocellular carcinoma progression.

Human hepatitis B virus (HBV) infection is the major cause of acute and chronic hepatitis B, liver cirrhosis, and hepatocellular carcinoma. Although the application of prophylactic vaccination programs has successfully prevented the trend of increasing HBV infection prevalence, the number of HBV-infected people remains very high. Approved therapeutic management efficiently suppresses viral replication; however, HBV infection is rarely completely resolved. The major reason for therapeutic failure is the persistence of covalently closed circular DNA (cccDNA), which forms viral minichromosomes by combining with histone and nonhistone proteins in the nucleus. Increasing evidence indicates that chromatin-modifying enzymes, viral proteins, and noncoding RNAs are essential for modulating the function of cccDNA. Therefore, a deeper understanding of the regulatory mechanism underlying cccDNA transcription will contribute to the development of a cure for chronic hepatitis B. This review summarizes the current knowledge of cccDNA biology, the regulatory mechanisms underlying cccDNA transcription, and novel anti-HBV approaches for eliminating cccDNA transcription.

Argininosuccinate lyase (ASL) plays an important role in the hepatic urea cycle, and can catalyze the reversible reaction of argininosuccinate to arginine and fumarate. However, the function of ASL in hepatocellular carcinoma (HCC) is not fully understood. In this study, we found that ASL expression was frequently upregulated in HCC tissues and HCC cell lines. Knock down of ASL inhibited cell proliferation and induced apoptosis in HCC cells. Mechanistic studies revealed the BCL2-associated X protein (Bax) signaling pathway which determines cancer cell apoptosis was regulated by ASL. Moreover, the depletion of Bax restored the inhibition of cell growth and reduced apoptosis initiated by ASL silencing. Together, the study demonstrated that ASL regulated HCC cell growth and apoptosis by modulating Bax signaling. Thus, the therapeutic targeting of ASL may offer options for HCC treatment.