Targeting <scp>C12ORF49</scp> ‐Mediated Ferroptosis in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for novel therapeutic strategies. Recent studies have highlighted the pivotal role of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, in cancer biology. C12ORF49, an emerging regulator of lipid metabolism, has gained attention for its influence on HCC cell survival and tumor progression. Specifically, C12ORF49 modulates the SREBP1/SCD1-mediated fatty acid metabolic pathway, which in turn suppresses ferroptosis, facilitating tumor cell survival and resistance to conventional therapies. Despite advances in understanding ferroptosis pathways, the complex interplay between lipid metabolism regulators like C12ORF49 and ferroptotic signaling in HCC remains incompletely understood. This review comprehensively summarizes current knowledge on the molecular mechanisms by which C12ORF49 intersects with ferroptosis signaling, highlighting its impact on lipid metabolic reprogramming in HCC. Furthermore, we explore the potential of targeting C12ORF49 to enhance the efficacy of existing treatments such as Sorafenib, a frontline systemic therapy for advanced HCC. By elucidating the crosstalk between C12ORF49 and ferroptosis pathways, this article aims to provide a theoretical framework and identify promising therapeutic targets for precision medicine approaches in hepatocellular carcinoma.