Post-Translational Modification Networks in Ferroptosis: Orchestrating Defense, Drug Resistance, and Therapeutic Opportunities in Hepatocellular Carcinoma

Abstract: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with therapeutic efficacy severely limited by drug resistance. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as a critical tumor-suppressive mechanism with particular relevance to HCC given the liver’s central role in iron homeostasis. Despite growing interest, a systematic examination of how post-translational modifications (PTMs) coordinately regulate ferroptotic susceptibility across all major defense systems and how this regulatory logic is exploited during drug resistance has been lacking. This review addresses this gap across four interconnected themes. We first dissect the three major ferroptosis defense systems in HCC—the system Xc − -GSH-GPX4 axis, the ACSL4-LPCAT3-PUFA peroxidation cascade, and the FSP1/CoQ10-DHODH parallel pathways—revealing that each node is governed by a combinatorial “PTMs code” involving ubiquitination, phosphorylation, acetylation, and lipid modifications that collectively determine the ferroptotic threshold. We then characterize iron metabolism reprogramming, demonstrating how the TFRC↑/FTH1↑/FPN1↓ triad creates an iron-rich milieu that primes tumor cells for ferroptotic execution while engaging pro-survival pathways through PTM-dependent mechanisms. A central focus is ferroptosis evasion as a unifying mechanism underlying resistance to sorafenib, lenvatinib, immunotherapy, and radiotherapy. We reveal that despite remarkable molecular diversity, resistance mechanisms converge on reinforcement of ferroptosis defense through multi-layered PTMs inputs—from NRF2-driven transcription and SLC7A11/GPX4 stabilization to recently discovered metabolite-sensitive modifications including lactylation, ISGylation, and O-GlcNAcylation. Emerging therapeutic strategies, including natural products, nanotechnology-based platforms, and rational drug combinations targeting the ubiquitin-proteasome system, are critically evaluated. Our synthesis highlights three key insights: (i) ferroptotic susceptibility is determined by the combinatorial state of multiple concurrent PTMs rather than any single modification; (ii) metabolite-sensitive PTMs serve as a molecular code linking the altered metabolic state of resistant cells directly to ferroptosis evasion; and (iii) the temporal hierarchy of PTMs deployment during resistance evolution defines a narrowing therapeutic window informing optimal intervention timing. Finally, we identify critical knowledge gaps and propose future directions for translating the PTMs-ferroptosis nexus into clinical benefit for HCC patients. Keywords: hepatocellular carcinoma, ferroptosis, post-translational modifications, drug resistance, iron metabolism, lipid peroxidation