Farnesol mitigates post-infarction ventricular remodeling via pharmacological modulation of the SPHK2/S1P/SMAD3 axis

Pathological ventricular remodeling following myocardial infarction (MI) is driven by dysregulated pro-fibrotic signaling and metabolic maladaptation. This study aimed to investigate whether farnesol, an endogenous mevalonate pathway intermediate with cardioprotective properties, mitigates post-MI fibrotic remodeling by pharmacologically modulating sphingolipid metabolism. MI was induced in C57BL/6 mice via permanent coronary artery ligation, followed by daily intragastric administration of farnesol (2 mg/kg) for 14 days. Cardiac structural and functional indices, alongside inflammatory and fibrotic cascades, were evaluated. The underlying molecular mechanisms were elucidated using transcriptomic and untargeted metabolomic profiling. In vivo target validation was achieved through pharmacological blockade of sphingosine kinase 2 (SPHK2) using opaganib. Farnesol treatment significantly preserved left ventricular systolic function and attenuated interstitial fibrosis. At the cellular level, farnesol facilitated inflammatory resolution by reducing acute neutrophil infiltration and promoting reparative M2 macrophage polarization, while restraining aberrant myofibroblast activation. Multi-omics integration revealed that farnesol modulated sphingolipid metabolism by selectively upregulating SPHK2 and increasing sphingosine-1-phosphate (S1P) synthesis. Activation of the SPHK2/S1P axis subsequently attenuated pro-fibrotic signaling via transforming growth factor-beta (TGF-β)/SMAD3. Crucially, targeted in vivo inhibition of SPHK2 with opaganib substantially reversed farnesol-induced suppression of SMAD3 and its downstream cardioprotective effects. These findings suggest that farnesol confers cardioprotection against post-MI remodeling, an effect closely associated with the pharmacological upregulation of the SPHK2/S1P axis and the subsequent attenuation of TGF-β/SMAD3-mediated fibrogenesis. Together, these findings highlight crosstalk between the mevalonate and sphingolipid pathways, supporting modulation of SPHK2 as a potential therapeutic strategy for the clinical management of post-MI heart failure.