Sodium Butyrate Attenuates Doxorubicin Sardiotoxicity Through GPR41/GPR43-Sox4-PI3K/Akt Signaling.

Abstract

Doxorubicin cardiotoxicity limits anthracycline chemotherapy, and mechanism-directed pharmacological protection remains limited. We investigated the cardioprotective action of sodium butyrate and its receptor-associated signaling mechanisms in doxorubicin-treated mice and H9c2 rat cardiomyoblasts. Targeted short-chain fatty acid profiling showed time- and compartment-dependent changes in endogenous butyrate after doxorubicin exposure. Oral sodium butyrate (300 mg/kg) improved left ventricular ejection fraction and fractional shortening, reduced circulating cardiac troponin I, creatine kinase-MB and lactate dehydrogenase, preserved myocardial ATP and mitochondrial ultrastructure, and decreased TUNEL positivity and the Bax/Bcl-2 ratio. In H9c2 cells, sodium butyrate (1 mM) increased viability and ATP content, preserved mitochondrial membrane potential, and reduced the Annexin V-positive fraction. Transcriptomic analysis and pathway perturbation implicated PI3K/Akt signaling. LY294002 attenuated sodium-butyrate-mediated protection in vivo and in vitro. GPR41 knockdown or GPR43 antagonism reduced cytoprotection and Akt phosphorylation. Sox4 loss- and gain-of-function experiments placed Sox4 upstream of Akt phosphorylation. A full-length Akt1 promoter reporter and co-immunoprecipitation further supported Sox4-associated transcriptional regulation and treatment-dependent co-precipitation of phosphorylated Akt with Sox4. These findings indicate that sodium butyrate attenuates doxorubicin cardiotoxicity through a receptor-associated Sox4-PI3K/Akt survival mechanism. Direct receptor-to-Sox4 coupling and direct Sox4 binding to the Akt1 promoter remain to be established.