Review discusses ACSL4 metabolic switch potential in hepatocellular carcinoma therapy strategies

Hepatocellular carcinoma (HCC) is characterized by profound lipid metabolic rewiring that supports tumor growth, therapeutic resistance, and immune evasion. Among lipid metabolic regulators, acyl-CoA synthetase long-chain family member 4 (ACSL4) has emerged as a pivotal determinant of polyunsaturated fatty acid (PUFA) activation and membrane phospholipid remodeling. Accumulating evidence reveals a functional duality of ACSL4 in HCC. On one hand, ACSL4 amplifies lipogenic transcriptional programs, enhances fatty acid oxidation–mediated energy adaptation, and cooperates with oncogenic signaling networks to promote tumor proliferation and survival, particularly under nutrient stress such as transarterial chemoembolization (TACE). On the other hand, ACSL4-driven enrichment of PUFA-containing phospholipids establishes the biochemical foundation for ferroptosis, sensitizing tumor cells to sorafenib and CD8+ T cell–mediated oxidative killing. This apparent paradox can be reconciled by conceptualizing ACSL4 as a context-dependent metabolic switch. Its biological output is dynamically tuned by therapeutic modality, microenvironmental redox conditions, post-transcriptional regulation (e.g., miR-23a-3p and miR-145-5p), post-translational modification (e.g., SIAH2-mediated ubiquitination), and substrate flux partitioning. Through these multilayered regulatory mechanisms, ACSL4 integrates lipid remodeling with ferroptotic sensitivity and tumor–immune interactions within the tumor microenvironment. In this mini-review, we synthesize recent mechanistic and translational findings to propose a unifying framework for ACSL4 function in HCC. Understanding ACSL4 as a metabolic switch rather than a static oncogenic factor may enable rational design of ferroptosis-enhancing and immunometabolic therapeutic strategies and support biomarker-guided precision medicine in HCC.