Bone marrow mesenchymal stem cells-derived exosomes ameliorate doxorubicin-induced nephrotoxicity via the modulation of pyroptosis-associated signaling

Abstract Doxorubicin (DOX) remains a cornerstone chemotherapeutic agent whose clinical application is constrained by nephrotoxicity, with no therapeutic interventions currently available. This study aimed to delineate the ameliorative potential of bone marrow mesenchymal stem cells (BM-MSCs) derived exosomes (EXO) in an experimental model of DOX-induced acute kidney injury (AKI). Twenty-four rats were divided into 4 groups: Control, DOX intoxicated, DOX + EXO, and EXO only groups. Nephrotoxicity was induced in the DOX and DOX + EXO groups using a single dose of DOX (15 mg/ kg i.p. ). After 24 h, DOX + EXO and EXO only groups were given BM-MSCs-derived exosomes (100 μg i.v. ). DOX was associated with a decline in renal function, activation of oxidative stress, inflammation, and modulation of pyroptosis-associated inflammasome-related signaling. BM-MSCs-derived exosomes significantly improved renal function, as evidenced by histopathological examination, reduction in KIM-1, blood urea nitrogen (BUN), serum creatinine, and renal somatic index (RSI). Exosomes mitigated oxidative stress by enhancing endogenous antioxidant catalase activity and reducing the lipid peroxidation marker MDA, while also suppressing inflammatory mediators, as shown by a reduction in IL-18 and IL-1β. Furthermore, exosomal treatment attenuated the expression of NLRP3, caspase-1 (CASP-1), and gasdermin-D (GSDMD), reduced ELAVL1, IRAK1 and NF-κB levels, while upregulating miR-146a-5p. In Silico analysis identified multiple putative molecular targets for miR-146a-5p, revealing strong interconnection among key targets, including ELAVL1, NF-κB, and IRAK1. These findings provide evidence to support the ameliorative role of BM-MSC-derived exosomes in mitigating DOX-induced AKI, associated with upregulation of miR-146a-5p and concurrent modulation of ELAVL1, IRAK1, and NF-κB, as well as NLRP3-associated inflammatory signaling, supporting the biological plausibility of a candidate miR-146a-5p/ELAVL1/IRAK1/NF-κB/NLRP3 regulatory network in AKI pathogenesis. Harnessing the reno-protective properties of exosomal therapy, as well as targeting the inflammasome-related signaling pathways, represents a compelling therapeutic paradigm warranting further mechanistic validation. Graphical Abstract DOX induces oxidative stress and kidney damage, activating the NF-κB pathway and the NLRP3 inflammasome, which in turn facilitates caspase-1-mediated pyroptosis and the secretion of inflammatory cytokines (IL-1β and IL-18). Exosomes containing miR-146a-5p mitigate this process by targeting IRAK1 and ELAVL1, consequently inhibiting NF-κB signaling, diminishing inflammasome activation, and safeguarding renal cells from inflammation and pyroptotic injury. DAMPs: Damage-associated molecular patterns; DOX: Doxorubicin; ELAVL1: ELAV-like RNA-binding protein 1; EXO: Exosomes; GSDMD: Gasdermin D; IL-18: Interleukin-18; IL-1β: Interleukin-1 beta; IRAK1: Interleukin-1 receptor associated kinase 1; NF-κB: Nuclear factor-kappa B; NLRP3: Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3; ROS: Reactive oxygen species; TLR: Toll-like receptor.