Background and Aims: The predominantly progressive, indeterminate, and predominantly regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes. Approach and Results: In an extension study on a randomized controlled trial, we originally enrolled 1000 patients with chronic hepatitis B and biopsy-proven histological significant fibrosis, and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, indeterminate, and regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of HCC was 1.5% for the regressive cases, 4.3% for the indeterminate cases, and 22.8% for the progressive cases (p<0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes, and Laennec staging, the posttreatment progressive had a HR of 17.77 (vs. posttreatment regressive; 95% CI: 5.55–56.88) for the incidence of liver-related events (decompensation, HCC, and death/liver transplantation). Conclusions: The P-I-R classification can be a meaningful complement to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.

INTRODUCTION: Liver fibrosis results from chronic liver injury and inflammation, often leading to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Progress has been made in understanding the molecular mechanisms underlying hepatic fibrosis; however, translating this knowledge into effective therapies for disease regression remains a challenge, with considerably few interventions having entered clinical validation. The roles of exosomes during fibrogenesis and their potential as a therapeutic approach for reversing fibrosis have gained significant interest. This study aimed to investigate the association between microRNAs (miRNAs) derived from serum exosomes and liver fibrosis and to evaluate the effect of serum exosomes on fibrogenesis and fibrosis reversal, while identifying the underlying mechanism. METHODS: Using serum samples collected from healthy adults and paired histologic patients with advanced fibrosis or cirrhosis, we extracted human serum exosomes by ultrahigh-speed centrifugation. Transcriptomic analysis was conducted to identify dysregulated exosome-derived miRNAs. Liver fibrosis–related molecules were determined by qRT-PCR, Western blot, Masson staining, and immunohistochemical staining. In addition, we analyzed the importance of serum exosome–derived miRNA expression levels in 42 patients with advanced fibrosis or cirrhosis. RESULTS: Exosome-derived miR-193a-5p and miR-381-3p were associated with fibrogenesis, as determined by transcriptomic screening. Compared with healthy control group, the high expression of serum exosome–derived miR-193a-5p and miR-381-3 in chronic hepatitis B (n = 42) was closely associated with advanced liver fibrosis and cirrhosis. In vitro , exosome-derived miRNA-193a-5p and miR-381-3p upregulated the expression of α-smooth muscle actin, collagen 1a1, and tissue inhibitors of metalloproteinase 1 in the human hepatic stellate cell line at both mRNA and protein levels. DISCUSSION: Serum exosome–derived miR-193a-5p and miR-381-3p regulated the adenosine 5'-monophosphate–activated protein kinase/transforming growth factor beta/Smad2/3 signaling pathway and promoted fibrogenesis.

Background: Clear cell renal cell carcinoma (ccRCC) is characterized by extensive lipid metabolic reprogramming that drives tumor progression and therapeutic resistance. Although sterol regulatory element-binding protein 1 (SREBP1) is a central regulator of lipogenesis in ccRCC, the upstream mechanisms governing its activation remain poorly defined. Here, we investigated the role of FAM120A in SREBP1-dependent lipid metabolism and evaluated the therapeutic potential of the natural product Soulangianolide A (SA). Methods: Stable knockdown of SREBP1 or FAM120A was established in ccRCC cells to assess lipid metabolism and malignant phenotypes. The antitumor activity and molecular mechanism of SA were investigated using integrated lipidomic, transcriptomic, proteomic, biochemical, and xenograft analyses, together with molecular docking, pull-down assays, surface plasmon resonance, and cellular thermal shift assays. Results: Genetic depletion of SREBP1 suppressed lipogenic gene expression, intracellular lipid accumulation, and malignant phenotypes in ccRCC cells. FAM120A promoted SREBP1 nuclear accumulation and transcriptional activity, whereas SA inhibited SREBP1 signaling, reduced lipid storage, and induced apoptosis. Multi-omics analyses revealed extensive metabolic remodeling characterized by depletion of triglycerides and membrane lipids, accompanied by accumulation of ceramides and acylcarnitines, indicative of a lipotoxic state. Mechanistically, SA directly bound FAM120A at Cys531, disrupted the FAM120A-SREBP1 complex, impaired SREBP1 nuclear activity, and consequently attenuated lipid-dependent PPARγ signaling. In xenograft models, SA significantly suppressed tumor growth, reduced intratumoral lipid accumulation, inhibited SREBP1-driven lipogenic signaling, and potentiated the antitumor efficacy of MK-6482. Conclusions: Our findings identify the FAM120A-SREBP1-PPARγ axis as a critical driver of lipid metabolic reprogramming in ccRCC, establish FAM120A as a direct molecular target of SA, and demonstrate that pharmacological disruption of this pathway effectively suppresses tumor growth. These findings provide a mechanistic rationale for targeting lipid metabolic reprogramming in ccRCC and support SA as a promising metabolism-targeted therapeutic strategy.