Repurposing Secukinumab and Dapagliflozin as Candidate Therapies to Mitigate the Renal Toxicity of Sunitinib in Rats Through Suppressing IL‐17‐Mediated Pyroptosis and Promoting Autophagy

ABSTRACT Sunitinib (SUN) is a chemotherapeutic agent showing renal toxicity that limits its clinical applications. The present research aimed to clarify the potential ameliorative effects of secukinumab (SEC) and dapagliflozin (DAPA) against SUN‐induced renal toxicity and the underpinning molecular mechanisms. For this purpose, adult Wistar albino rats were received SUN (25 mg/kg 3 times/week, po ) and co‐treated with SEC (3 mg/kg/every 2 weeks, subcutaneously) or DAPA (10 mg/kg/day, po ) for 4 weeks and compared with age‐matched control group (CON). Markers of kidney functions were assessed in serum samples. Kidneys were harvested for biochemical and histological examination. Compared to CON group, SUN‐treated rats displayed signs of kidney dysfunction along with renal histological changes that were ameliorated by SEC or DAPA. Both drugs significantly lowered the renal levels of IL‐17, but SEC exerted more inhibitory effect than DAPA. Additionally, SUN‐subjected rats showed significant increases in the renal expression of NLRP3 inflammasome and the other inflammatory mediators including IL‐1β, END‐1, and MCP‐1. This was associated with marked decline of the renal levels of beclin‐1. Co‐treatment with SEC or DAPA significantly suppressed NLRP3‐induced inflammation while enhanced beclin‐1‐mediated autophagy. The modulatory effect of DAPA on NLRP3 and beclin‐1 was superior to that of SEC. Moreover, both drugs significantly and similarly attenuated the enhanced cleaved caspase‐3 expression and interstitial fibrosis in renal tissue of SUN‐subjected rats. Collectively, these findings may repurpose SEC and DAPA as candidate therapies to alleviate the renal toxicity of SUN and to rescue the renal functionality in SUN‐treated cancer cases.