SAMHD1 deficiency disrupts macrophage autophagy-lysosomal homeostasis and promotes inflammation via the mTOR-MITF-CTSD axis in ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by dysregulated immune responses and macrophage-driven inflammation. In this study, we identify SAMHD1 (SAM domain and HD domain-containing protein 1) as a critical regulator of macrophage homeostasis in UC. Single-cell RNA sequencing (scRNA-seq) of colonic tissues revealed reduced SAMHD1 expression in UC-associated macrophages. Using myeloid-specific SAMHD1-deficient mice, we demonstrate that SAMHD1 loss exacerbates colonic inflammation, promotes M1 macrophage polarization, and activates the NF-κB pathway. Mechanistically, SAMHD1 deficiency impairs autophagy-lysosomal flux by enhancing Microphthalmia-associated transcription factor (MITF) nuclear translocation and suppressing the expression of its downstream target, cathepsin D (CTSD). Pharmacological inhibition of the PI3K/AKT/mTOR pathway restores MITF-CTSD signaling, improves lysosomal function, and alleviates colitis symptoms. Furthermore, rapamycin treatment significantly reduces inflammation in SAMHD1-deficient mice. These findings highlight the SAMHD1-MITF-CTSD axis as a pivotal regulator of macrophage-mediated inflammation in UC and suggest mTOR inhibition as a promising therapeutic strategy for SAMHD1-related colitis.