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Background and Aims: Promoting liver regeneration while inhibiting fibrogenesis represented an attractive strategy for treating liver diseases, with HSCs being crucial to both processes. This study aimed to identify specific targets in HSCs that simultaneously facilitated regeneration and suppressed fibrosis, and elucidated their molecular mechanisms., Approach and Results: Through comparing acute and chronic liver injury mouse models induced by CCl 4 injections, we revealed that HSCs exhibited dual functionality, expressing pro-regenerative and profibrogenic genes following injury. Analyzing RNA-seq data from primary HSCs of these models, along with publicly available single-cell RNA-seq data of HSCs, we identified transcription factor Lhx2, specifically expressed in HSCs, as a potential regulator of the dual functions. Notably, Lhx2 showed significantly higher expression in HSCs from healthy liver tissue compared to fibrotic liver, in both mouse and human models. Lhx2 knockdown impaired liver function recovery and cellular proliferation after acute liver injury. Consistent changes were observed in mice with HSC-specific Lhx2 overexpression. In addition, Lhx2 overexpression not only promoted hepatocyte proliferation but also exhibited an antifibrogenic function after chronic injury. Mechanistically, Lhx2 suppressed multiple functions of activated HSCs, including fibrogenesis, proliferation, and migration, and upregulated SMAD6 to block the TGF-β signaling pathway. Moreover, Lhx2 was an upstream regulator of various pro-regenerative factors, especially HGF, which is crucial for liver regeneration., Conclusions: We demonstrated that Lhx2 had pro-regenerative and antifibrogenic functions, and elucidated its regulatory mechanism. The study provided a potential target with dual effects for treating liver diseases., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: To improve the prognosis of advanced intrahepatic cholangiocarcinoma (iCCA), we retrospectively compared the effect and safety of combined hepatic arterial infusion chemotherapy (HAIC), targeted therapy and immunotherapy with systemic chemotherapy (SC) in unresectable iCCA patients., Methods: We retrospectively enrolled 202 advanced iCCA patients treated with SC or targeted therapy, immunotherapy, and FOLFOX-HAIC combined between March 2015 and June 2023 at our institution. 202 patients were divided into two groups based on the therapeutic regimens. Baseline characteristics and prognosis were reviewed and analyzed., Results: After 1-to-1 propensity score matching, 76 patients were included in each group. The triple combination therapy group demonstrated longer median overall survival (OS, 20.77 vs. 14.83 months, P=0.047), progression-free survival (PFS, 9.07 vs. 6.23 mo, P<0.001), intrahepatic PFS (11.03 vs. 6.73 mo, P<0.001), extrahepatic PFS (11.37 vs. 7.13 months, P=0.0064), and a higher objective response rate (35.5% vs. 14.5%, P=0.003) than the SC group. Fever, thrombocytopenia, elevated ALT, elevated AST, hypoalbuminemia, and hyperbilirubinemia were more common adverse events (AEs) in the triple combination therapy group, while fatigue and anemia were more prevalent in the SC group (P<0.05). For grades 3-4 AEs, the rates of elevated ALT were higher in the triple combination group (P=0.028)., Conclusions: Compared with SC, triple combination therapy comprising HAIC, targeted therapy and immunotherapy appears to be an effective and safe treatment for advanced iCCA., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To assess the clinical value of the pretherapeutic systemic inflammation score (SIS) in predicting the prognosis of hepatocellular carcinoma (HCC) after hepatic arterial infusion chemotherapy (HAIC)., Methods: From February 2016 to April 2021, 415 advanced HCC patients who underwent HAIC at Sun Yat-sen University Cancer Center were randomly divided into training (n = 277) and validation cohorts (n = 138) and analyzed. The aspartate aminotransferase-alanine aminotransferase ratio (AAR), lymphocyte × albumin (L × A), and neutrophil × monocyte (N × M) were used to construct the SIS score based on a multivariate Cox analysis in the training cohort. A nomogram consisting of the SIS score was created and evaluated by calibration plot, areas under the receiver operating characteristic (AUC) curve, and decision curve analysis (DCA)., Results: Univariate and multivariate Cox analyses revealed that the SIS score was an independent predictor of OS. A high SIS score was associated with large tumor size (P < 0.05), multiple lesions (P < 0.01), high AFP level (P < 0.01), extrahepatic metastasis (P < 0.05), and advanced BCLC stage (P < 0.01). Kaplan-Meier analysis showed that the patients with a high SIS had shorter OS than those with a low SIS in both the non-PD (p = 0.015) and PD group (p = 0.023). The calibration plots showed good concordance between the nomogram's prediction and the actual observations in both the training and validation cohorts. In the training cohort, the AUCs of the nomogram predicting the 2-year and 3-year survival rates were 0.749 and 0.739, respectively; in the validation cohort, they were 0.760 and 0.681, respectively. Based on the AUC and DCA, the nomogram showed better predictive ability than other predictors., Conclusion: The pretherapeutic SIS score is a potential prognostic predictor for HCC patients undergoing HAIC., Competing Interests: All authors declare that they have no competing interests in this work., (© 2023 Wu et al.)