Wang Shunxi, Yuan Xiaoxue, Yang Zetao, Zhang Xuan, Xu Zhiling, Yang Li, Yang Xian, Zhou Wei, Liu Wanqian
Key Laboratory of Biorheological Science and Technology, Ministry of Education& 111 Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China.
Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China; Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
J Adv Res. 2025 Jul;73:265-282. doi: 10.1016/j.jare.2024.08.021. Epub 2024 Aug 17.
INTRODUCTION: Heterogeneous tissue stiffening promotes tumor progression and resistance, and predicts a poor clinical outcome in patients with hepatocellular carcinoma (HCC). Ferroptosis, a congenital tumor suppressive mechanism, mediates the anticancer activity of various tumor suppressors, including immune checkpoint inhibitors, and its induction is currently considered a promising treatment strategy. However, the role of extracellular matrix (ECM) stiffness in regulating ferroptosis and ferroptosis-targeted resistance in HCC remains unclear. OBJECTIVES: This research aimed to explore how extracellular matrix stiffness affects ferroptosis and its treatment efficacy in HCC. METHODS: Ferroptosis analysis was confirmed via cell activity, intracellular ferrous irons, and mitochondrial pathology assays. Baseline PD-L2, SMYD3, and SLC7A11 (xCT) were evaluated in 67 sorafenib-treated patients with HCC (46 for non-responder and 21 for responder) from public data. The combined efficacy of shPD-L2, sorafenib, and anti-PD-1 antibody in HCC was investigated in vivo. RESULTS: Here, we revealed that matrix stiffness-induced PD-L2 functions as a suppressor of xCT-mediated ferroptosis to promote cancer growth and sorafenib resistance in patients with HCC. Mechanically, matrix stiffening induced the expression of PD-L2 by activating SMYD3/H3K4me3, which acts as an RNA binding protein to enhance the mRNA stability of FTL and elevate its protein level. Knockdown of PD-L2 significantly promoted xCT-mediated ferroptosis induced by RSL3 or sorafenib on stiff substrate via FTL, whereas its overexpression abolished these upward trends. Notably, PD-L2 deletion in combination with sorafenib and anti-PD-1 antibody significantly sensitized HCC cells and blunted cancer growth in vivo. Additionally, we found the ferroptosis- and immune checkpoint-related prognostic genes that combined PD-L2, SLC7A11 and SYMD3 well predict the clinical efficacy of sorafenib in patients with HCC. CONCLUSION: These findings expand our understanding of the mechanics-dependent PD-L2 role in ferroptosis, cancer progression and resistance, providing a basis for the clinical translation of PD-L2 as a therapeutic target or diagnostic biomarker.
引言：异质性组织硬化促进肿瘤进展和耐药，并预示着肝细胞癌（HCC）患者的临床预后不良。铁死亡是一种先天性肿瘤抑制机制，介导包括免疫检查点抑制剂在内的多种肿瘤抑制因子的抗癌活性，目前诱导铁死亡被认为是一种有前景的治疗策略。然而，细胞外基质（ECM）硬度在调节HCC中铁死亡及铁死亡靶向耐药方面的作用仍不清楚。 目的：本研究旨在探讨细胞外基质硬度如何影响HCC中铁死亡及其治疗效果。 方法：通过细胞活性、细胞内亚铁离子和线粒体病理学检测来确认铁死亡分析。从公开数据中评估了67例接受索拉非尼治疗的HCC患者（46例无反应者和21例反应者）的基线PD-L2、SMYD3和SLC7A11（xCT）水平。在体内研究了shPD-L2、索拉非尼和抗PD-1抗体联合治疗HCC的疗效。 结果：在此，我们揭示了基质硬度诱导的PD-L2作为xCT介导的铁死亡的抑制剂，促进HCC患者的肿瘤生长和索拉非尼耐药。机制上，基质硬化通过激活SMYD3/H3K4me3诱导PD-L2表达，SMYD3作为一种RNA结合蛋白，增强FTL的mRNA稳定性并提高其蛋白水平。敲低PD-L2可通过FTL显著促进RSL3或索拉非尼在硬基质上诱导的xCT介导的铁死亡，而其过表达则消除了这些上升趋势。值得注意的是，PD-L2缺失联合索拉非尼和抗PD-1抗体可显著使HCC细胞敏感并抑制体内肿瘤生长。此外，我们发现联合PD-L2、SLC7A11和SYMD3的铁死亡和免疫检查点相关预后基因能很好地预测索拉非尼对HCC患者的临床疗效。 结论：这些发现扩展了我们对机械依赖的PD-L2在铁死亡、肿瘤进展和耐药中的作用的理解，为将PD-L2作为治疗靶点或诊断生物标志物的临床转化提供了依据。
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