Ultrasound targeted microbubble destruction-assisted mesoporous silicon delivery of dexamethasone inhibits ulcerative colitis by regulating the MTDH/ACSL4/NF-κB pathway.

Abstract

AIMS: This study aims to elucidate the role of acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated ferroptosis in ulcerative colitis (UC). Furthermore, we evaluated the therapeutic efficacy of dexamethasone (DEX)-loaded hollow mesoporous silica nanoparticles (HMSN@DEX) in combination with ultrasound-targeted microbubble destruction (UTMD) to enhance targeted delivery and achieve synergistic treatment effects. MATERIALS AND METHODS: The therapeutic performance of HMSN@DEX was assessed using cell cultures and mouse models. UTMD was employed to facilitate targeted delivery, with the underlying ACSL4-mediated ferroptosis mechanism analyzed across multiple biological levels. KEY FINDINGS: Our research shows that inhibition of ACSL4 prevents ferroptosis death of intestinal epithelial cells and attenuates experimental colitis in mice. Mechanistically, Metadherin (MTDH) regulate the ubiquitination of ACSL4 by binding with Lys37 thus interfere the interaction between ACSL4 and MARCHF6, while simultaneously activating NF-κB signaling. Moreover, MTDH knockdown ameliorate ferroptosis in IECs induced by erastin and this effect can be counteract by ACSL4-WT. When the lys37 was mutated with K37A, ACSL4-K37A cannot achieve this effect. Further, the combination of UTMD and HMSN@DEX possess better colonic drug accumulation in the colon of mice with colitis. In both cellular and murine models of colitis, the UTMD+HMSN@DEX has better therapeutics effect than free dexamethasone or HMSN@DEX alone by regulating the MTDH/ACSL4/NF-κB pathway. SIGNIFICANCE: Our research reveals the critical role of the MTDH/ACSL4/NF-κB signaling pathway in regulating intestinal ferroptosis. The combination of UTMD and HMSN@DEX achieved the most significant attenuation in colitis among the three delivery strategies.