由代谢功能障碍相关脂肪性肝炎 (MASH) 引起的肝细胞癌 (HCC) 提出了重大的临床挑战，特别是考虑到西方饮食 (WD) 的盛行。饮食对肿瘤微环境的影响仍然知之甚少。半乳糖凝集素-1 (Gal-1) 是 HCC 的生物标志物，在肝癌发生中发挥着至关重要的作用。我们之前的研究表明，沉默 Gal-1 可以有效治疗小鼠 HCC。然而，WD 对 Gal-1 信号传导对 MASH 向 HCC 进展的影响尚不清楚，本研究解决了这些知识空白。我们开发了一种新型 MASH-HCC 小鼠模型。利用空间转录组学和多重免疫组织化学 (IHC)，我们研究了 WD 对肝脏和肿瘤微环境的影响。通过沉默和过度表达来调节 Gal-1 表达，我们探索了 WD 对 Gal-1 信号传导的位置特异性影响。Rho 信号传导、细胞外基质 (ECM) 重塑和衰老相关分泌表型 (SASP) 等途径最为显着。与健康肝脏对照相比，WD 诱导的代谢功能障碍相关脂肪肝 (MAFLD) 和 MASH-HCC 中被激活。此外，Rho GTPase 效应子、ECM 重塑、中性粒细胞脱粒、细胞应激和细胞周期途径在人和小鼠 MASH-HCC 中持续丰富。在空间上，这些通路在小鼠 MASH-HCC 的肿瘤和肿瘤边缘富集。此外，从非肿瘤组织到肿瘤边缘和 MASH-HCC 肿瘤内部的 CD11c 和 PD-L1 阳性细胞显着增加，表明摄入 WD 导致免疫监视受损。此外，MASH-HCC 在 N-钙粘蛋白阳性细胞中表现出显着的 Gal-1 诱导，表明上皮间质转化 (EMT) 增强。调节 MASH-HCC 中的 Gal-1 表达进一步确立了其在调节 MASH-HCC 肿瘤边缘和非肿瘤组织中的 Rho 信号传导和 SASP 中的特定作用。WD 摄入显着影响参与 Gal-1 介导的信号传导的重要细胞过程，包括肿瘤微环境中的 Rho 信号传导和 ECM 重塑，从而促进 MASH-HCC 的发展。© 2024。作者。

Hepatocellular carcinoma (HCC) arising from metabolic dysfunction-associated steatohepatitis (MASH) presents a significant clinical challenge, particularly given the prevalence of the Western diet (WD). The influence of diet on the tumor microenvironment remains poorly understood. Galectin-1 (Gal-1) is a biomarker for HCC and has a crucial role in liver carcinogenesis. Our previous studies demonstrated that silencing Gal-1 effectively treats mouse HCC. However, the impacts of a WD on Gal-1 signaling on MASH to HCC progression are unknown, and this study addresses these knowledge gaps.We developed a novel MASH-HCC mouse model. Using spatial transcriptomics and multiplex immunohistochemistry (IHC), we studied the effects of a WD on the liver and tumor microenvironment. By modulating Gal-1 expression through silencing and overexpression, we explored the location-specific impacts of WD on Gal-1 signaling.Pathways such as Rho signaling, extracellular matrix (ECM) remodeling, and senescence-associated secretory phenotypes (SASP) were prominently activated in WD-induced metabolic dysfunction-associated fatty liver disease (MAFLD) and MASH-HCC, compared to healthy livers controls. Furthermore, Rho GTPase effectors, ECM remodeling, neutrophil degranulation, cellular stress, and cell cycle pathways were consistently enriched in human and mouse MASH-HCC. Spatially, these pathways were enriched in the tumor and tumor margins of mouse MASH-HCC. Additionally, there was a notable increase in CD11c and PD-L1-positive cells from non-tumor tissues to the tumor margin and inside the tumor of MASH-HCC, suggesting compromised immune surveillance due to WD intake. Moreover, MASH-HCC exhibited significant Gal-1 induction in N-Cadherin-positive cells, indicating enhanced epithelial-to-mesenchymal transition (EMT). Modulating Gal-1 expression in MASH-HCC further established its specific roles in regulating Rho signaling and SASP in the tumor margin and non-tumor tissues in MASH-HCC.WD intake significantly influences vital cellular processes involved in Gal-1-mediated signaling, including Rho signaling and ECM remodeling, in the tumor microenvironment, thereby contributing to the development of MASH-HCC.© 2024. The Author(s).