Kaempferol Ameliorates Sepsis‐Acute Lung Injury by Promoting Succinylation of SRPK1

Sepsis is the leading cause of acute lung injury (ALI), and kaempferol has a protective effect against ALI. However, the underlying mechanisms have not been fully elucidated. This study aimed to investigate the role of kaempferol in sepsis-induced ALI and its underlying molecular mechanism, particularly the involvement of succinylation. Human pulmonary microvascular endothelial cells were treated with lipopolysaccharide to induce injury. Cell apoptosis and inflammation were evaluated by flow cytometry and enzyme-linked immunosorbent assay. Succinylation was analysed using immunoblotting, co-immunoprecipitation and protein stability assay. The results showed that kaempferol inhibited apoptosis and inflammation response in LPS-treated HPMVECs and attenuated lung damage in septic mice. Moreover, kaempferol enhanced succinylation levels and reduced SIRT5 protein levels. SIRT5 suppressed the succinylation of SRPK1 at lysine (K) 588 site and facilitated SRPK1 degradation. Overexpression of SIRT5 or knockdown of SRPK1 reversed the inhibitory effects of kaempferol or SIRT5 knockdown on cellular biological behaviours, respectively. In conclusion, kaempferol attenuates sepsis-induced lung injury by inhibiting HPMVEC apoptosis and inflammation. Mechanistically, kaempferol suppresses SIRT5-mediated desuccinylation of SRPK1, thereby promoting SRPK1 protein stability. The findings suggest the important role of SRPK1 succinylation in ALI and kaempferol may be used for the treatment of the disease.