Stearoyl-CoA desaturase 1 integrates tissue-specific oncogenic pathways into a pan-cancer ferroptosis resistance program

: Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has recently emerged as a promising therapeutic vulnerability in cancer. Among its key modulators, stearoyl-CoA desaturase 1 (SCD1) plays a pivotal role in ferroptosis resistance by converting saturated fatty acids into monounsaturated fatty acids (MUFAs), thereby limiting the accumulation of highly peroxidizable polyunsaturated fatty acids (PUFAs) and stabilizing membrane integrity under oxidative stress. Multiple oncogenic, transcriptional, epigenetic, and microenvironmental cues enhance tumor survival by promoting SCD1-dependent ferroptosis resistance. Despite this diversity of regulatory inputs, a unifying principle emerges across tumor types: SCD1 activity preserves lipid desaturation as a dominant metabolic strategy to suppress ferroptotic cell death. In this review, we critically analyze how SCD1-dependent ferroptosis resistance is shaped by tumor-specific metabolic states, microenvironmental pressures, and regulatory hierarchies across multiple malignancies. We identify recurring mechanistic themes through which SCD1 integrates redox control, lipid metabolism, stemness, and therapy resistance, while highlighting how these processes are differentially regulated across tissues. Preclinical evidence indicates that targeting SCD1, particularly in rational combination with ferroptosis inducers, chemotherapy, radiotherapy, or immunotherapy, can lower the ferroptotic threshold and overcomes treatment resistance. Finally, we discuss translational challenges and emerging strategies, including tumor-selective delivery, adaptive dosing, and context-specific combinations, that may enable safe and effective exploitation of the SCD1-ferroptosis axis in cancer therapy.