BACKGROUND AND AIMS:Liver fibrosis, when dysregulated, contributes to irreversible loss of hepatic structure and function, heralding end-stage liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) represent the common progenitor to myofibroblasts that produce extracellular matrix proteins to mediate liver fibrosis. In the present study, we investigated the role of Pre-B-cell leukemia transcription factor 1 (PBX1) in this process. APPROACH AND RESULTS:PBX1 was screened out of mining through liver fibrosis-related single-cell RNA-seq data sets as the most prominently upregulated transcription factor during HSC activation. Ingenuity pathway analysis, coupled with reporter assay and chromatin immunoprecipitation assay, demonstrated that Notch3 mediated the elevation of PBX1 expression at the transcriptional level in HSCs. PBX1 knockdown attenuated HSC-myofibroblast transition in vitro and liver fibrosis in mice. Integrated transcriptomic analysis suggested that PBX1 contributed to HSC activation by activating a host of pro-fibrogenic molecules, including IL-7 receptor (IL7R/CD127). Consistently, exposure to recombinant IL-7 promoted HSC activation, whereas IL7R knockdown hampered HSC activation. Mechanistically, IL7R interacted with TGF-β receptors (I/II) to trigger a pro-fibrogenic signaling cascade. Importantly, blockade of the IL-7-IL7R signaling with neutralizing antibodies markedly ameliorated liver fibrosis in mice. Finally, a positive correlation between PBX1, IL7R, and HSC activation was identified in patients with cirrhosis. CONCLUSIONS:Our data uncover a previously unappreciated role for PBX1 in HSC activation and provide proof of concept for targeting IL-7 signaling in the intervention of liver fibrosis.
BACKGROUND AND AIMS:Clinically significant portal hypertension in patients with liver cirrhosis can lead to refractory ascites. A TIPS treats clinically significant portal hypertension but may cause overt hepatic encephalopathy (oHE). Our aim was to determine the optimal reduction of the portal pressure gradient (PPG) through TIPS to control ascites without raising oHE risk. APPROACH AND RESULTS:This multicenter study screened 1509 patients from 3 European centers (Hannover, Vienna, and Hamburg) undergoing TIPS implantation between 2000 and 2023. Patients with TIPS indications other than refractory ascites/hepatic hydrothorax, vascular liver disease, HCC, or insufficient PPG data were excluded. PPG was measured before and after TIPS insertion. Outcome data were assessed up to 1 year after TIPS insertion. Analyses were conducted utilizing a modern machine learning model, namely a competing-risk random survival forest, partial dependence plots, and competing risk analyses with liver transplantation/death as competitors. The cohort was divided into a 60% derivation and 40% validation cohort. Overall, 729 patients (median MELD: 13 [IQR 10-16], 66% male, 23% oHE before TIPS) were analyzed. The derivation cohort comprised 438 patients, and the validation cohort comprised 291 patients. The optimal PPG reduction, determined by maximally selected Gray statistic and PDP of the random survival forest, was 60%-80%. In this range, patients showed significantly fewer hepatic decompensations due to ascites (HDA) (subdistribution hazard ratio [sHR]: 0.7 [0.52-0.96]) with similar oHE incidences (sHR: 0.92 [0.67-1.27]). The PPG range was confirmed in the validation cohort (HDA: sHR: 0.66 [0.46-0.96]; oHE: sHR: 0.89 [0.61-1.32]). CONCLUSIONS:A targeted PPG reduction of 60%-80% showed significantly reduced HDA without increased oHE risk. Therefore, PPG reduction within this range could be a valid reduction target.
Lactate plays a critical role as an energy substrate, metabolite, and signaling molecule in hepatocellular carcinoma (HCC). Intracellular lactate-derived protein lysine lactylation (Kla) is identified as a contributor to the progression of HCC. Liver cancer stem cells (LCSCs) are believed to be the root cause of phenotypic and functional heterogeneity in HCC. However, the impact of Kla on the biological processes of LCSCs remains poorly understood. Here enhanced glycolytic metabolism, lactate accumulation, and elevated levels of lactylation are observed in LCSCs compared to HCC cells. H3K56la was found to be closely associated with tumourigenesis and stemness of LCSCs. Notably, a comprehensive examination of the lactylome and proteome of LCSCs and HCC cells identified the ALDOA K230/322 lactylation, which plays a critical role in promoting the stemness of LCSCs. Furthermore, this study demonstrated the tight binding between aldolase A (ALDOA) and dead box deconjugate enzyme 17 (DDX17), which is attenuated by ALDOA lactylation, ultimately enhancing the regulatory function of DDX17 in maintaining the stemness of LCSCs. This investigation highlights the significance of Kla in modulating the stemness of LCSCs and its impact on the progression of HCC. Targeting lactylation in LCSCs may offer a promising therapeutic approach for treating HCC.
目的:探讨布比卡因对肝癌HepG2细胞增殖、侵袭、凋亡及微小RNA-191(miR-191)/Krüppel样因子6(KLF6)信号轴的影响.方法:设肝癌HepG2细胞组、顺铂组(3.0 μg/ml)、布比卡因低剂量组(2.5 mg/ml)、布比卡因高剂量组(5.0 mg/ml).培养72 h后,测定肝癌HepG2细胞存活率、穿膜数、凋亡率、miR-191、KLF6 mRNA和蛋白水平.结果:与肝癌HepG2细胞组比较,顺铂组、布比卡因低、高剂量组肝癌HepG2细胞存活率、穿膜数、miR-191水平降低,凋亡率、KLF6 mRNA和蛋白水平升高(P＜0.05);与顺铂组比较,布比卡因低、高剂量组肝癌HepG2细胞存活率、穿膜数、miR-191水平升高,凋亡率、KLF6 mRNA和蛋白水平降低(P＜0.05);与布比卡因低剂量组比较,布比卡因高剂量组肝癌HepG2细胞存活率、穿膜数、miR-191水平降低,凋亡率、KLF6 mRNA和蛋白水平升高(P＜0.05).结论:布比卡因能明显抑制肝癌HepG2细胞增殖和侵袭,促进其凋亡;其机制可能与布比卡因降低肝癌HepG2细胞中miR-191的表达进而促进KLF6的表达有关.
关于肝病治法,我国现存医学文献最早的经典著作《内经》记载了治肝的基本法则,至清代王旭高所著《西溪书屋夜话录》之"治肝三十法",粲然可观.后张锡纯作《医学衷中参西录》,基于《内经》对肝病的治法多有创建,书中所载医案大多信息详尽,脉证分明,且附有作者的辨证思路,更有助于我们理解并学习其学术特点.
