Polygalasaponin F alleviates cerebral ischemia-reperfusion injury through inhibiting mitophagy

Neurological recovery after ischemic stroke (IS) remains clinically challenging, primarily due to cerebral ischemia-reperfusion injury (CIRI). Oxidative stress contributes to the pathogenesis of CIRI by causing reactive oxygen species excessive accumulation, which disrupts mitochondrial function. Mitophagy maintains mitochondrial function by eliminating damaged or dysfunctional mitochondria. Nevertheless, mitophagy exerts dual effects, either excessive or insufficient activation exacerbates mitochondrial dysfunction. Polygalasaponin F (PGSF), a natural triterpenoid saponin, has been demonstrated to regulate mitochondrial function. Therefore, in this study, we investigated whether PGSF protects against CIRI through inhibiting the mitophagy in vitro and in vivo. Results showed that PGSF attenuated apoptosis both in vivo and in vitro. Moreover, PGSF preserved mitochondrial membrane potential (MMP), reduced mitochondrial reactive oxygen species (mtROS), and ameliorated mitochondrial morphology to improve mitochondrial function in vitro. Furthermore, we revealed that PGSF ameliorates CIRI via modulation of mitophagy, evidenced by a reduced LC3II/LC3I ratio, decreased colocalization of LC3 with mitochondria, while enhancing the levels of TOM20 and p62. In conclusion, our findings imply that PGSF alleviates CIRI through inhibiting mitophagy and reducing apoptosis, demonstrating its therapeutic potential.