肝脏对慢性代谢应激的适应导致肿瘤的发生，这一成果由麻省理工学院Alex K. Shalek研究团队经过不懈努力而取得。相关论文于2025年12月22日发表在《细胞》杂志上。
通过跨物种纵向单细胞多组学，研究组发现持续的压力驱动非转化肝细胞的预后发育和癌症相关程序，同时降低其成熟的功能特征。创建综合计算方法，该课题组人员确定并实验验证干扰肝细胞功能平衡的主要调节因子，在压力下增加增殖，并直接引发未来的肿瘤发生。通过对人体组织微阵列空间转录组学的地理回归，研究小组揭示了空间结构的多细胞群落和形成应激反应的信号相互作用。他们的工作揭示了细胞对慢性应激的早期解决方案如何能够为未来的肿瘤发生和结果提供基础，将围绕核心可操作机制的细胞功能障碍的多种模式统一起来。
据悉，在慢性应激状态下，细胞既要维持组织功能，又要维持自身生存。肝细胞具有代谢、合成和解毒作用，但慢性营养失衡可诱导肝细胞死亡并诱发代谢功能障碍相关的脂肪性肝炎（MASH，以前称为NASH）。尽管先前的研究发现了应激诱导的肝细胞死亡驱动因素，但慢性应激对存活细胞的功能影响仍不清楚。
附：英文原文
Title: Hepatic adaptation to chronic metabolic stress primes tumorigenesis
Author: Constantine N. Tzouanas, Jessica E.S. Shay, Marc S. Sherman, Adam J. Rubin, Benjamin E. Mead, Tyler T. Dao, Junyan Tao, Brandon M. Lehrich, George Eng, Jeffrey Patterson-Fortin, Titus Butzlaff, Miyeko D. Mana, Kellie E. Kolb, Chad Walesky, Brian J. Pepe-Mooney, Colton J. Smith, Sanjay M. Prakadan, Michelle L. Ramseier, Yuzhou Evelyn Tong, Julia Joung, Fangtao Chi, Thomas McMahon-Skates, Carolyn L. Winston, Woo-Jeong Jeong, Katherine J. Aney, Ethan Chen, Sahar Nissim, Feng Zhang, Vikram Deshpande, Satdarshan P. Monga, Georg M. Lauer, Wolfram Goessling, mer H. Yilmaz, Alex K. Shalek
Issue&Volume: 2025-12-22
Abstract: During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Despite prior work identifying stress-induced drivers of hepatocyte death, chronic stress’ functional impact on surviving cells remains unclear. Through cross-species longitudinal single-cell multi-omics, we show that ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing their mature functional identity. Creating integrative computational methods, we identify and then experimentally validate master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. Through geographic regression on human tissue microarray spatial transcriptomics, we uncover spatially structured multicellular communities and signaling interactions shaping stress responses. Our work reveals how cells’ early solutions to chronic stress can prime future tumorigenesis and outcomes, unifying diverse modes of cellular dysfunction around core actionable mechanisms.
DOI: 10.1016/j.cell.2025.11.031
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01366-2