基于泛癌视角的ACSL1研究进展：脂质代谢 重编程、铁死亡与治疗应答

Research Progress of ACSL1 from a Pan-Cancer Perspective: Lipid Metabolic Reprogramming, Ferroptosis, and Therapeutic Response

摘要: ACSL1是长链脂肪酸活化和代谢分流的重要调控分子，在脂肪酸β-氧化、甘油三酯合成、膜脂重塑及氧化应激稳态维持中发挥关键作用。近年来，随着肿瘤代谢研究的不断深入，ACSL1在肿瘤中的作用逐渐受到关注。现有研究表明，ACSL1不仅参与肿瘤脂质代谢重编程，还与脂质过氧化、铁死亡敏感性及治疗应答密切相关，但其生物学效应具有明显的癌种依赖性和情境依赖性。本文从泛癌视角系统综述ACSL1的分子特征与基本功能，重点总结其在肿瘤脂质代谢重编程中的作用，以及其在肝细胞癌、卵巢癌、前列腺癌、透明细胞肾细胞癌、结直肠癌、乳腺癌、胶质瘤、肺癌和慢性髓系白血病等不同肿瘤中的研究进展。总体来看，ACSL1在肝细胞癌、卵巢癌、前列腺癌和乳腺癌中更倾向于参与异常脂质代谢维持、转移潜能增强及治疗耐受形成；在透明细胞肾细胞癌中则更可能具有抑制肿瘤样或保护性作用；而在结直肠癌、胶质瘤、肺癌及血液系统肿瘤中，其作用方向仍受具体分子背景和证据强度限制，尚需进一步验证。已有研究还提示，ACSL1可通过调控脂质过氧化和铁死亡阈值，参与铂类、乐伐替尼及内分泌治疗等治疗反应。此外，本文进一步讨论了ACSL1作为生物标志物和治疗靶点的临床转化挑战，包括mRNA与蛋白检测层级差异、功能性翻译后修饰、表达阈值标准化、肿瘤内异质性以及缺乏亚型特异性抑制剂等问题，并结合现有机制证据提出多种潜在联合治疗策略。综上，ACSL1并非单纯的脂质代谢酶，而更应被视为连接脂质代谢重编程、铁死亡调控和治疗应答的情境依赖性代谢枢纽。未来仍需通过更多功能实验、空间组学及临床转化研究，进一步阐明其癌种特异性作用及分子基础，以评估其作为生物标志物和治疗靶点的临床应用价值。

Abstract: ACSL1 is a key regulator of long-chain fatty acid activation and metabolic partitioning and plays essential roles in fatty acid β-oxidation, triacylglycerol synthesis, membrane lipid remodeling, and maintenance of oxidative stress homeostasis. With the rapid development of cancer metabolism research, increasing attention has been paid to the role of ACSL1 in malignant tumors. Current evidence indicates that ACSL1 is not only involved in lipid metabolic reprogramming, but is also closely associated with lipid peroxidation, ferroptosis sensitivity, and therapeutic response. However, its biological effects are highly cancer-type-dependent and context-dependent. This review summarizes the molecular characteristics and basic functions of ACSL1 from a pan-cancer perspective, with a focus on its role in tumor lipid metabolic reprogramming and its emerging significance in hepatocellular carcinoma, ovarian cancer, prostate cancer, clear cell renal cell carcinoma, colorectal cancer, breast cancer, glioma, lung cancer, and chronic myeloid leukemia. Overall, ACSL1 tends to contribute to aberrant lipid metabolic maintenance, enhanced metastatic potential, and therapeutic tolerance in hepatocellular carcinoma, ovarian cancer, prostate cancer, and breast cancer. In contrast, in clear cell renal cell carcinoma, ACSL1 appears more likely to exert tumor-restraining or protective effects. In colorectal cancer, glioma, lung cancer, and hematologic malignancies, the direction of its action remains incompletely defined and is still influenced by molecular background and the strength of current evidence. Available studies also suggest that ACSL1 may participate in therapeutic response to platinum agents, lenvatinib, and endocrine therapy by modulating lipid peroxidation and the threshold of ferroptosis. In addition, this review further discusses the translational challenges of ACSL1 as a biomarker and therapeutic target, including discrepancies between mRNA- and protein-level detection, functional post-translational modifications, standardization of expression thresholds, intratumoral heterogeneity, and the current lack of isoform-specific inhibitors. Based on existing mechanistic evidence, several potential combination therapeutic strategies are also proposed. Collectively, ACSL1 should not be regarded merely as a lipid metabolic enzyme, but rather as a context-dependent metabolic hub linking lipid metabolic reprogramming, ferroptosis regulation, and therapeutic response. Future studies integrating functional experiments, spatial omics, and translational investigations are still required to further elucidate the cancer type-specific roles and molecular basis of ACSL1, thereby facilitating the evaluation of its clinical potential as a biomarker and therapeutic target.