Progesterone Receptor Membrane Component 1 (PGRMC1), also known as S2R (sigma-2 receptor), is a heme-binding protein. It has a central role in supporting cytochrome P450 activity and is associated with multiple pathways, such as heme homeostasis, lipid and drug metabolism, hormone signaling, and cholesterol synthesis [1,6,7]. It is involved in various biological processes including female reproduction, protein quality control, and has significance in cancer development [1]. Genetic models are valuable for studying its functions.

In the context of cancer, PGRMC1-dependent lipophagy promotes ferroptosis in paclitaxel-tolerant persister cancer cells. PGRMC1 silencing reduces ferroptosis sensitivity, while its overexpression increases ferroptosis, suggesting its role in cancer cell death regulation [2]. In breast cancer, PGRMC1 expression in tissue is correlated with tumor characteristics, and patients with PGRMC1-positive tumors have poorer survival. It may also be a predictive marker for breast cancer risk during hormone replacement therapy [3]. In non-small cell lung cancer (NSCLC), PGRMC1 overexpression enhances cancer stem cell phenotypes and chemotherapy resistance by disrupting TRIM56-mediated ubiquitination of AHR [4]. In triple-negative breast cancer, PGRMC1 promotes cell growth by suppressing ferroptosis through binding to intracellular iron [5]. In heart failure, PGRMC1 ablation protects from energy-starved heart failure by promoting fatty acid/pyruvate oxidation, indicating its role in cardiac metabolism [8].

In conclusion, PGRMC1 is a multifunctional protein involved in numerous biological processes and disease conditions. Gene knockout (KO) or conditional knockout (CKO) mouse models, though not explicitly detailed in all references, would further elucidate its role in specific disease areas such as cancer and heart failure. Understanding PGRMC1 functions through model-based research provides insights into disease mechanisms and potential therapeutic targets.