SIRT7-mediated desuccinylation of FOXO4 suppresses ferroptosis to alleviate LPS-induced acute lung injury.

Protein succinylation, an emerging post-translational modification (PTM), assumes a crucial role in the initiation and advancement of inflammatory diseases. Ferroptosis, propelled by lethal lipid peroxidation, is intricately associated with the pathogenesis of inflammation. Targeting ferroptosis has recently emerged as a promising therapeutic approach for acute lung injury (ALI). Nevertheless, the crosstalk between protein succinylation and ferroptosis in the regulation of ALI remains ambiguous. FOXO4, a key regulator of oxidative stress responses, is dynamically regulated by various PTMs. We identify SIRT7 as the desuccinylase essential for FOXO4 activation and nuclear localization. Mechanistically, SIRT7 desuccinylates FOXO4 at lysine 139 (K139), thereby inhibiting MDM2-mediated K48-linked polyubiquitination, which stabilizes FOXO4 and maintains FOXO4 nuclear retention. This consequently upregulates glutathione peroxidase 4 (GPX4) and suppresses lipopolysaccharide (LPS)-induced ferroptosis in alveolar epithelial cells (AECs). In vivo experiments demonstrated that SIRT7-knockout (SIRT7-KO) exacerbates LPS-induced ALI. Furthermore, the delivery of a FOXO4-K139R (mimicking desuccinylation) via adeno-associated virus 6 (AAV6) significantly alleviated pulmonary ferroptosis and histopathological damage in SIRT7-KO mice. Notably, pharmacological activation of SIRT7 with trilobatin (TLB) significantly attenuates ALI in LPS-challenged mice, establishing a potential therapeutic pathway for this pathology. Collectively, these findings delineate a previously unrecognized mechanism through which SIRT7 governs the nuclear retention and activation of FOXO4 via desuccinylation, establishing the SIRT7-FOXO4 axis as a potential therapeutic target and theoretical basis for ALI intervention.