SLC25A39: A key regulator of mitochondrial metabolism and a promising therapeutic target in cancer

The mitochondrial solute carrier (SLC25) family regulates solute transport across the mitochondrial inner membrane. Among them, SLC25A39 has emerged as a critical player in tumor biology, primarily through its dual role in mediating mitochondrial glutathione (mGSH) transport and maintaining iron-sulfur cluster homeostasis. Recent evidence implies that SLC25A39 dysfunction disrupts mGSH metabolism, thereby influencing iron-sulfur cluster synthesis and driving metabolic reprogramming in tumors. Notably, SLC25A39 is governed by a GSH-Fe-S-AFG3L2 feedback circuit, a feature not shared by its closest homolog SLC25A40. Additionally, upregulation of SLC25A39 is frequently observed in multiple malignancies, including colorectal, pancreatic, and liver cancers, where it correlates with enhanced proliferation, metastasis, and poor prognosis. Furthermore, SLC25A39 expression is intricately associated with remodeling of the tumor immune microenvironment and the development of therapeutic resistance, although these associations are primarily based on correlative evidence and require functional validation before causal conclusions can be drawn. This review synthesizes current knowledge on the molecular mechanisms by which SLC25A39 integrates mGSH transport with iron metabolism, and critically evaluates its emerging roles across different cancer types. We propose that beyond serving as a candidate prognostic biomarker, SLC25A39 represents a potential therapeutic target whose clinical utility remains to be established, and we discuss key unanswered questions regarding its tissue-specific functions and the translational challenges that lie ahead.