Mitochondrial transporter SLC25A39 emerges as a metabolic hub and candidate target in cancer

A mitochondrial transporter once barely on the radar of cancer researchers has moved to the center of a rapidly expanding body of work on tumor metabolism. SLC25A39, a member of the solute carrier family 25 that shuttles metabolites across the mitochondrial inner membrane, is the subject of a new review published in Medical Oncology that synthesizes evidence gathered largely since 2021. The review, led by Tian Tian, Yan Jin, Penghua Cui and Suwei Lan, argues that SLC25A39 sits at a junction between glutathione transport, iron-sulfur cluster assembly and cancer cell survival, and that its frequent overexpression in solid tumors makes it both a candidate prognostic biomarker and a potential therapeutic target whose clinical value remains unproven.

The protein’s defining role emerged from a CRISPR-Cas9 screen reported by Wang and colleagues, which identified SLC25A39 and its close homolog SLC25A40 as the primary transporters responsible for importing glutathione into the mitochondrial matrix. Glutathione is synthesized in the cytoplasm, but roughly 10 to 15 percent of a cell’s total pool resides inside mitochondria, where it neutralizes reactive oxygen species generated during oxidative phosphorylation and protects sensitive metabolic machinery from oxidative damage. Genetic deletion of SLC25A39 in cultured cells caused a dramatic drop in mitochondrial glutathione without depleting total cellular glutathione, confirming the transporter’s specific import function. The consequences of that loss are substantial: increased mitochondrial ROS, impaired oxidative phosphorylation, reduced proliferation and heightened sensitivity to apoptotic stimuli. In animal models, SLC25A39 deficiency has been associated with mitochondrial defects, neurodegeneration and anemia, underscoring its essential role in normal physiology.

Structurally, SLC25A39 follows the canonical architecture of the SLC25 family, the largest group of mitochondrial transporters in humans with 53 known members. The gene sits on chromosome 17q21.31, spans about 40 kilobases across eight exons, and encodes a 396-amino-acid precursor of roughly 43 kilodaltons; after cleavage of the N-terminal mitochondrial targeting sequence, the mature 359-amino-acid protein runs at approximately 39 kilodaltons on SDS-PAGE. Three tandem repeats of about 100 amino acids each form two transmembrane helices, assembling into a six-helix bundle with a central cavity that serves as the substrate translocation pathway. What sets SLC25A39 apart from most family members is a matrix-facing domain containing four conserved cysteine residues that act as sensors for iron-sulfur clusters, a feature its closest homolog SLC25A40 lacks. Tissue profiling shows the protein is ubiquitously expressed but most abundant in liver, kidney, heart, testis and spleen, consistent with a role in supporting oxidative metabolism.

Those cysteines are the key to what the review’s authors call the GSH-Fe-S-AFG3L2 regulatory axis, a proposed feedback circuit that links glutathione availability to iron-sulfur cluster biogenesis. According to the model, SLC25A39 imports glutathione into the matrix; the mitochondrial glutathione pool supports the synthesis of iron-sulfur clusters; abundant clusters then bind the four conserved cysteines, triggering a conformational change that shields SLC25A39 from degradation by the mitochondrial AAA+ protease AFG3L2. When iron-sulfur clusters are scarce, the protection disappears and AFG3L2 rapidly degrades the transporter, throttling glutathione import and further limiting cluster synthesis. Studies by Shi and colleagues and Liu and colleagues established that AFG3L2 promotes SLC25A39 degradation and that iron-sulfur clusters modulate this process through the cysteine residues. The authors are careful to note, however, that while each mechanistic step has experimental support, the complete circuit operating as a self-regulating loop in vivo remains a proposed model rather than a definitively established mechanism. Notably, SLC25A40 is not governed by this loop and may instead play a complementary housekeeping role, with recent work showing that it sustains electron transport chain integrity and promotes cytokine production in macrophages.

The stakes of this circuitry are high because iron-sulfur clusters are essential cofactors for enzymes spanning the tricarboxylic acid cycle, respiratory complexes I, II and III, and DNA replication and repair. Mitochondrial glutathione supports cluster biogenesis in two ways: by maintaining a redox environment that protects the oxidation-prone active-site cysteines of the ISC machinery components NFS1 and ISCU, and by serving as a thiol reservoir that can furnish cysteine equivalents for NFS1-dependent persulfide generation. Depleting mitochondrial glutathione impairs iron-sulfur-dependent enzymes such as aconitase, a defect that can be rescued by mitochondrially targeted glutathione biosynthesis. The review also flags a purely hypothetical extension: because hypoxia-inducible factor 1-alpha is regulated by iron-dependent prolyl hydroxylases rather than iron-sulfur proteins, disrupted cluster synthesis could in principle perturb iron availability and stabilize HIF-1α, but this connection has not been tested experimentally.

Against this mechanistic backdrop, tumor biology data have accumulated quickly. Bioinformatic analyses of The Cancer Genome Atlas and other datasets show SLC25A39 significantly upregulated in colorectal cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, breast cancer, ovarian cancer and head and neck squamous cell carcinoma, generally correlating with advanced stage and poor survival. Functional studies go further in several settings. In colorectal cancer, overexpression promoted proliferation, migration and colony formation while suppressing apoptosis through reduced ROS driven by enhanced mitochondrial glutathione import, and knockdown suppressed xenograft tumor growth in mice. In breast cancer cells, overexpression accelerated mitochondrial fission, shifting the balance of Fis1 and Mfn1 expression in a direction associated with invasiveness and metastatic potential, though the link between the transporter’s import function and the fission machinery remains unresolved. In ovarian cancer, SLC25A39-mediated glutathione import maintained energy metabolism and redox homeostasis, potentiating the RXFP1/cAMP/PKA/CREB axis and driving metabolic reprogramming and tumor progression.

Pancreatic cancer has produced one of the most striking findings. Liu and colleagues showed that SLC25A39 confers resistance to cuproptosis, a recently identified form of copper-induced cell death in which copper binds lipoylated TCA cycle proteins and triggers proteotoxic stress. Treatment with the cuproptosis inducer elesclomol plus copper activated the transcription factor NFE2L2, which upregulated the glutathione biosynthesis genes GCLM and GCLC; the newly made glutathione was then imported into mitochondria by SLC25A39, where it chelated copper and prevented its interaction with lipoylated proteins. Genetic or pharmacological inhibition of this NFE2L2-glutathione-SLC25A39 pathway sensitized pancreatic cancer cells to cuproptosis and suppressed tumor growth in xenograft models. In hepatocellular carcinoma, two independent functional studies showed that SLC25A39 stabilizes the peroxiredoxin PRDX1 to suppress necroptosis and, separately, that its glutathione import protects cells from ferroptosis, with loss of the transporter restoring responsiveness to the first-line drug sorafenib in cell models.

The review is notably cautious about the tumor immune microenvironment. Several bioinformatic analyses report associations between SLC25A39 expression and immune infiltration patterns, including reduced CD8-positive T cells in hepatocellular carcinoma and lower immune scores and checkpoint molecule expression in colorectal cancer, patterns consistent with an immune-evasive, potentially immunotherapy-resistant state. The authors deliberately use the term association rather than regulation, emphasizing that all available evidence is correlative, that no study has directly linked SLC25A39-mediated metabolic changes to immune cell recruitment or function, and that no intervention studies in immunocompetent animal models have been reported. Because adaptive anti-tumor T cell responses cannot be evaluated in xenograft models, they argue that experiments in immunocompetent mice with SLC25A39 knockdown or overexpression are indispensable before any causal claims about immune modulation can be made.

Translational prospects come with significant caveats. High SLC25A39 expression consistently predicts poor prognosis across epithelial malignancies, and multivariate analysis in the TCGA hepatocellular carcinoma cohort identified it as an independent risk factor for overall survival, but prospective validation is lacking. A complicating case comes from soft tissue sarcomas, where a single reported patient carried a novel germline SLC25A39 mutation across multiple histologically distinct tumors, while mutations in the TCGA sarcoma dataset are extremely rare at 0.78 percent of cases, contrasting with the overexpression phenotype seen in carcinomas. Therapeutic targeting faces further barriers: SLC25A39 is normally expressed at relatively high levels in liver, kidney and heart, raising on-target toxicity concerns, no selective small-molecule inhibitors exist, and SLC25A40 redundancy may buffer normal tissues. The authors propose synthetic lethality strategies, PROTAC-based degraders that disrupt the AFG3L2 interaction rather than the transporter itself, and patient stratification by expression level as the most promising paths forward, while stressing that rigorous preclinical comparisons in clinically relevant models must precede any clinical translation.

Subject of Research: The role of the mitochondrial transporter SLC25A39 in glutathione transport, iron-sulfur cluster homeostasis and cancer biology

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

Article References: Tian, T., Jin, Y., Cui, P., & Lan, S. (2026). SLC25A39: A key regulator of mitochondrial metabolism and a promising therapeutic target in cancer. Medical Oncology, 43(11), Article 356. https://doi.org/10.1007/s12032-026-03466-5

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03466-5

Keywords: SLC25A39, mitochondrial glutathione, iron-sulfur clusters, AFG3L2, cuproptosis, ferroptosis, tumor metabolism, pancreatic cancer, hepatocellular carcinoma, colorectal cancer, therapeutic target, prognostic biomarker