Wijayasiri Pramudi, Astbury Stuart, Needham Grace, Kaye Philip, Bhat Mamatha, Piccinini Anna M, Aravinthan Aloysious D
NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.
Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, E Floor, West Block, QMC Campus, Derby Road, Nottingham, NG7 2UH, UK.
Hum Cell. 2025 Mar 18;38(3):70. doi: 10.1007/s13577-025-01201-2.
Accumulation of senescent hepatocytes is universal in chronic liver disease (CLD). This study investigates an association between hepatocyte senescence and hepatocellular carcinoma (HCC) and explores the therapeutic role of sirolimus. Background liver biopsies from 15 patients with cirrhosis and HCC and 45 patients with cirrhosis were stained for p16, a marker of cell senescence. STAM™ mice were randomized into 3 groups of 5 at 4 weeks of age and administered vehicle ± sirolimus intraperitoneally, thrice weekly, from 4 to 18 weeks of age. Placebo group was an administered vehicle, early sirolimus group was an administered vehicle with sirolimus, late sirolimus group was an administered vehicle from 4 to 12 weeks then vehicle with sirolimus from 12 to 18 weeks. The primary outcome was HCC nodule development. Senescent hepatocyte burden and senescence-associated secretory phenotype (SASP) factors were assessed in mice livers. In the human study, age (OR 1.282, 95% CI 1.086-1.513, p = 0.003) and p16 (OR 1.429, 95% CI 1.112-1.838, p = 0.005) were independently associated with HCC. In the animal study, all three groups exhibited similar MASLD activity scores (p = 0.39) and fibrosis area (p = 0.92). The number and the maximum diameter of HCC nodules were significantly lower in the early sirolimus group compared to placebo and late sirolimus group. The gene expression of SASP factors was similar in all groups. Protein levels of some SASP factors (TNFα, IL1β, IL-2, CXCL15) were significantly lower in sirolimus administered groups compared to placebo group. The study demonstrates an independent association between senescent hepatocyte burden and HCC. It indicates a potential chemoprophylactic role for sirolimus through SASP factor inhibition. These early results could inform a future human clinical trial.
衰老肝细胞的积累在慢性肝病（CLD）中普遍存在。本研究调查了肝细胞衰老与肝细胞癌（HCC）之间的关联，并探讨了西罗莫司的治疗作用。对15例肝硬化合并HCC患者和45例肝硬化患者的背景肝活检组织进行细胞衰老标志物p16染色。STAM™小鼠在4周龄时随机分为3组，每组5只，从4周龄到18周龄每周三次腹腔注射溶剂±西罗莫司。安慰剂组注射溶剂，早期西罗莫司组注射溶剂加西罗莫司，晚期西罗莫司组在4至12周注射溶剂，12至18周注射溶剂加西罗莫司。主要结局是HCC结节的形成。评估小鼠肝脏中的衰老肝细胞负荷和衰老相关分泌表型（SASP）因子。在人体研究中，年龄（OR 1.282，95%CI 1.086 - 1.513，p = 0.003）和p16（OR 1.429，95%CI 1.112 - 1.838，p = 0.005）与HCC独立相关。在动物研究中，所有三组的代谢相关脂肪性肝病（MASLD）活动评分（p = 0.39）和纤维化面积（p = 0.92）相似。与安慰剂组和晚期西罗莫司组相比，早期西罗莫司组的HCC结节数量和最大直径显著更低。所有组中SASP因子的基因表达相似。与安慰剂组相比，西罗莫司给药组中一些SASP因子（TNFα、IL1β、IL - 2、CXCL15）的蛋白水平显著更低。该研究证明了衰老肝细胞负荷与HCC之间的独立关联。它表明西罗莫司通过抑制SASP因子具有潜在的化学预防作用。这些早期结果可为未来的人体临床试验提供参考。
