4-Octyl itaconate attenuates renal calculi formation by inhibiting ferroptosis and oxidative stress via the Nrf2-HO-1/SLC7A11 axis.

BACKGROUND

Calcium oxalate (CaOx) kidney stones are the most common form of urolithiasis and are characterized by high incidence and recurrence rates. 4-Octyl itaconate (4-OI), an itaconate derivative, has been shown to exert broad protective effects in various disease models owing to its anti-inflammatory and antioxidant properties. However, its role in CaOx kidney stone formation remains largely unknown.

METHODS AND

RESULTS

A CaOx kidney stone model was established in 6-week-old male C57BL/6 mice by glyoxylic acid induction, followed by treatment with 4-OI at 50 mg/kg. Renal tissues were subjected to HE, TUNEL, DHE, Prussian blue, and von Kossa staining to evaluate renal tissue injury, apoptosis, reactive oxygen species (ROS) production, iron deposition, and CaOx crystal deposition. Mechanistically, we observed that 4-OI exerts its effects through the NRF2-HO-1/SLC7A11 pathway in HK-2 cells. Our results suggest that 4-OI prevents CaOx crystal formation, attenuates oxidative stress, and mitigates ferroptosis both in vitro and in vivo via the NRF2-HO-1/SLC7A11 pathway.

CONCLUSION

4-OI attenuates renal CaOx formation, reduces oxidative stress, and alleviates ferroptosis through the NRF2-HO-1/SLC7A11 pathway. These findings suggest that 4-OI has significant therapeutic potential for the treatment of CaOx kidney stones.