<p>Sennoside A (SA), a frequently-used powerful laxative in clinic. Although the protective effect of SA has been recognized in digestive diseases, diabetes and nephropathy, it is still unclear whether it exerts the protective function in sepsis-induced acute kidney injury (AKI). The research aimed to disclose the regulatory mechanism of SA in sepsis-associated AKI. We utilized the cecal ligation and puncture (CLP) and by administering SA (15, 30 and 60&#xa0;mg/kg), and employing HE and TUNEL staining of the pathological changes of kidney tissue. Detecting BUN and Creatinine levels to evaluate kidney dysfunction. By using ELISA and western blotting assays, Fe²⁺, ACSL4, GPX4, MDA, GSH, IL-6, TNF-α and IL-1β were detected to assess the function of SA in sepsis-triggered ferroptosis, oxidative stress and inflammatory response. SIRT1, Ac-NF-κB p65 and Ac-Foxo1 protein levels were investigated to unearth the regulatory mechanisms. SA ameliorated kidney histological damage and kidney function in sepsis-induced AKI mice. SA inhibited ferroptosis and oxidative stress through declining Fe²⁺ level, elevating GPX4 and GSH levels, but suppressing ACSL4 and MDA levels. IL-6, TNF-α and IL-1β levels were reduced by SA administration in sepsis mice. In terms of mechanism, SIRT1 expression was dramatically enhanced by SA, leading to a reduction of downstream molecules (Ac-NF-κB p65 and Ac-Foxo1). Ultimately, the protective function of SA was abrogated by SIRT1 inhibitor (EX527). SA played a protective role in sepsis-induced AKI by regulating SIRT1 pathway. This innovative research mechanism might provide theoretical foundation for sepsis-triggered AKI treatment.</p>