{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Acyl‐CoA synthetase long‐chain family member 4 (ACSL4) is a key metabolic enzyme that preferentially activates polyunsaturated fatty acids—such as arachidonic acid—and channels them into membrane phospholipids. This biochemical “trapping” generates oxidizable substrates that fuel lipid peroxidation and thereby critically drive ferroptotic cell death. A series of studies have demonstrated that aberrant ACSL4 expression modulates cellular sensitivity to ferroptosis in numerous contexts including cancer and ischemia/reperfusion injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Moreover, ACSL4 activity is tightly regulated by transcription factors and kinases—for instance, Sp1‐mediated transcriptional upregulation and PKCβII‐dependent phosphorylation both promote its activation and set in motion a feed‐forward loop that amplifies ferroptotic lipid peroxidation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In tumor biology, the expression level of ACSL4 has emerged as a critical determinant of ferroptosis sensitivity. For example, reduced ACSL4 in glioma cells is associated with resistance to ferroptotic triggers"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", whereas its elevated expression sensitizes cancer cells—such as in ovarian cancer—to glutathione peroxidase 4 (GPX4) inhibitors and other ferroptosis inducers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Beyond its role in ferroptosis, ACSL4 also contributes to broader aspects of lipid metabolism in cancer. In hepatocellular carcinoma, for instance, ACSL4 drives de novo lipogenesis by upregulating the master regulator sterol regulatory element-binding protein 1 (SREBP1) via a c-Myc-dependent pathway"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and in colon adenocarcinoma, its overexpression modulates arachidonic acid metabolism to favor tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In prostate cancer, increased ACSL4—resulting from noncoding RNA–mediated derepression—has been implicated in the development of docetaxel resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the pivotal role of ACSL4 in linking lipid metabolic reprogramming with the execution of ferroptosis and diverse oncogenic processes. The modulation of ACSL4 activity or expression thus represents a promising therapeutic target for a range of diseases, from solid tumors to ischemia-induced tissue injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hua Yuan, Xuemei Li, Xiuying Zhang, et al. 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