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

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. Graphical Abstract Doxorubicin induces acute cardiotoxicity characterized by impaired cardiac function, mitochondrial injury, reduced ATP production, and increased cardiomyocyte apoptosis. During the acute phase, circulating butyrate levels increase, whereas myocardial butyrate levels decrease, indicating a transient imbalance in butyrate distribution. Sodium butyrate supplementation attenuates doxorubicin-induced cardiac injury and improves mitochondrial and cellular function. Mechanistically, the protective effects of sodium butyrate are implicated in‌ GPR41/GPR43-associated regulation of Sox4 and subsequent activation of PI3K/Akt signaling, resulting in reduced apoptotic signaling and enhanced cardiomyocyte survival. The GPR41/GPR43-Sox4-PI3K/Akt pathway shown here represents a proposed mechanism supported by the present pharmacological and molecular evidence