源自癌细胞的细胞外囊泡（EV）是肿瘤进展过程中细胞间通讯的重要介质。肿瘤来源的 EV 中的货物有助于建立肿瘤支持性微环境，可以作为改善癌症治疗的治疗靶点。在这里，我们证明了肝细胞癌（HCC）细胞在大细胞外囊泡（lEV）中分泌酰基辅酶A合成酶ACSL4来调节肿瘤-微环境相互作用，从而促进HCC进展。 HCC衍生的lEV ACSL4增加了细胞内含有多不饱和脂肪酸的脂质的丰度，并重塑了脂质谱，从而增强了瘤周肝细胞中的脂质过氧化，导致肝细胞衰老并伴有衰老相关的分泌表型（SASP）。通过衰老治疗消除衰老肝细胞可抑制肿瘤进展。在 HCC 细胞中，SREBP2 介导的转录激活上调 ACSL4 表达，Akt 介导的 ACSL4 磷酸化通过增强其与膜联蛋白 A2 的相互作用诱导其包装到 lEV 中。这项研究确定了 HCC 细胞分泌的 ACSL4 在诱导肝细胞脂质重塑和衰老以支持 HCC 进展方面的关键调节功能，表明靶向 lEV ACSL4 是 HCC 的潜在治疗策略。

Extracellular vesicles (EVs) derived from cancer cells are crucial mediators of intercellular communication during tumor progression. The cargo in tumor-derived EVs that facilitates the establishment of a tumor-supportive microenvironment could serve as a therapeutic target to improve cancer treatment. Here, we demonstrated that hepatocellular carcinoma (HCC) cells secreted the acyl-CoA synthetase ACSL4 in large extracellular vesicles (lEVs) to modulate tumor-microenvironment interactions that promote HCC progression. HCC-derived lEV ACSL4 increased the intracellular abundance of polyunsaturated fatty acid-containing lipids and remodeled the lipid profile to potentiate lipid peroxidation in peritumoral hepatocytes, resulting in hepatocyte senescence accompanied by the senescence-associated secretory phenotype (SASP). Depletion of senescent hepatocytes by senolytic treatment suppressed tumor progression. In HCC cells, SREBP2-mediated transcriptional activation upregulated ACSL4 expression, and Akt-mediated phosphorylation of ACSL4 induced its packaging into lEVs by augmenting its interaction with Annexin A2. This study identified the critical regulatory function of ACSL4 secreted from HCC cells in inducing lipid remodeling and senescence in hepatocytes to support HCC progression, suggesting that targeting lEV ACSL4 is a potential therapeutic strategy for HCC.