Unraveling MARCH6's role in cancer progression and metabolism from protein homeostasis to oncogenesis.

Malignant neoplasms are a leading cause of morbidity and mortality globally, with rising rates despite advancements in detection and treatment. This review examines the multifaceted role of MARCH6, an endoplasmic reticulum-resident E3 ubiquitin ligase, in cancer biology and disease regulation. MARCH6 exhibits a complex, context-dependent dual role: it functions as a pro-oncogenic driver in papillary thyroid carcinoma (PTC) and hepatocellular carcinoma (HCC), where it promotes cell proliferation and metastatic potential, yet simultaneously serves protective roles in non-malignant pathological conditions, including the regulation of ferroptosis, a form of iron-dependent lipid peroxidation-driven cell death, and antiviral immunity. In particular, emerging evidence suggests that MARCH6 can modulate ferroptosis through the selective degradation of key regulators such as p53 and ACSL4, thereby linking ubiquitin-mediated proteostasis to redox balance and lipid metabolism. The review synthesizes current understanding of MARCH6's structure, substrate specificity, and tissue-specific functional outcomes, emphasizing the molecular determinants of its context-dependent activity across different cellular contexts. Particular attention is given to MARCH6's regulatory impact on cholesterol and lipid metabolism, oxidative stress responses, and cell death mechanisms, with ferroptosis positioned as a central mechanistic axis through which MARCH6 may influence tumor progression and therapeutic response. Despite these mechanistic advances, critical knowledge gaps persist regarding substrate selectivity across diverse cancer types, the molecular basis of functional polarity, and therapeutic feasibility. This synthesis aims to guide future research toward harnessing MARCH6's potential as a biomarker and selective therapeutic target in cancer and stress-related diseases, particularly in the context of ferroptosis modulation, while acknowledging the inherent challenges in targeting its context-dependent functions.