Targeted inhibition of MX1 attenuates podocyte ferroptosis and ameliorates pristane-induced lupus nephritis.

Lupus nephritis (LN) represents a severe renal complication of systemic lupus erythematosus (SLE). Myxovirus resistance 1 (MX1) has been reported to play an important role in the development of kidney injury, however, its specific function in pristane-induced LN remains unclear. In this study, we determined that pristane-treated MX1-knockout mice resulted in attenuated renal histopathological injury, reduced serum levels of anti-RNP antibody and IgG, inhibited concentrations of blood creatinine and urea nitrogen, along with suppressed expression of inflammatory mediators compared with pristane-treated wild-type mice (p = 0.0497, 0.0435, 0.0043, 0.0364, 0.0403, 0.0477 and 0.0375, respectively). GEO analysis highlighted alterations in oxidative stress and lipid metabolic pathways related to ferroptosis in LN patients. Both in vivo and in vitro pristane-induced injury models demonstrated that suppression of MX1 alleviates ferroptosis, as evidenced by reduced intracellular iron accumulation, malondialdehyde levels, and reactive oxygen species generation, accompanied by an elevated glutathione/glutathione disulfide ratio, enhanced activity of superoxide dismutase, and upregulation of ACSL4, GPX4, PTGS2, and SLC7A11 (p = 0.0464, 0.0437, 0.0337, 0.0425, 0.0494, 0.0266, 0.0423 and 0.0430, respectively). Furthermore, MX1 inhibition improved mitochondrial function and increased the expression of key mitochondrial biogenesis regulators, including UCP2, MFN2, PGC1α, and TFAM (p = 0.0251, 0.0468, 0.0391 and 0.0022, respectively). These results indicate that targeting MX1 confers protection against pristane-induced LN by inhibiting podocyte ferroptosis.