SLC22A4 as a candidate regulator linking immunity and ferroptosis in septic shock.

Septic shock is a life-threatening syndrome characterized by immune dysregulation, oxidative injury, and high mortality. To identify candidate regulators linking immunity and ferroptosis in septic shock, we integrated expression quantitative trait loci (eQTL)-based Mendelian randomization (MR) with transcriptomic datasets from septic shock patients and controls. Differentially expressed genes overlapping with MR-prioritized genes were further evaluated using 113 machine-learning models, among which the glmBoost plus elastic net model (alpha = 0.9) showed strong discriminatory performance, with area under the curve (AUC) values of 0.999 in GSE26378, 0.980 in GSE26440, and 0.987 in the meta-cohort. The final model retained four risk genes, SERPINB1, DDAH2, SLC22A4, and CEACAM6. Among them, SLC22A4/OCTN1, an ergothioneine transporter, was associated with neutrophil-related immune features and better survival-related outcomes, whereas CEACAM6 showed a distinct pattern associated with immune dysregulation. Protein-ligand docking predicted potential interactions between candidate compounds and selected target proteins. In neutrophil-based validation experiments, SLC22A4 perturbation altered inflammatory cytokine production, STING-associated signaling readouts, and ferroptosis-related markers. Additional transporter-related assays showed that SLC22A4 knockdown reduced intracellular ergothioneine accumulation and that ergothioneine supplementation partially rescued erastin-induced viability loss and lipid ROS accumulation. In a cecal ligation and puncture (CLP) model, D-carnitine hydrochloride, STING-IN-5, and Keap1-Nrf2-IN-9 reshaped inflammatory cytokine responses and were associated with partial attenuation of septic lung injury. These findings suggest that SLC22A4 may represent a candidate regulator connecting immune remodeling with ferroptosis-associated dysfunction in septic shock; however, independent cohort validation, direct in vivo target-engagement studies, and further mechanistic analyses are required before therapeutic translation.