Hich is triggered by either extrinsic or intrinsic stimuli (Radak et al., 2017). The intrinsic stimuli for apoptosis are by way of a series of mitochondrial signaling pathways (Yu et al., 2020b). Huang et al. discovered that HSYA enhanced viability of brain microvascular endothelial cells (BMECs) immediately after OGD/R (Huang et al., 2021). On top of that, HSYA decreased the export of cytochrome c from mitochondrial by inhibiting mPTP opening by means of the regulation of MEK/ERK/CypD pathway in each OGD/R and MCAO models (Huang et al., 2021). Moreover, HSYA was identified to improve mitochondrial function and biogenesis by way of inhibiting phenylalanine synthesis in OGD/ R-injured primary neurons and PC12 cells (Chen et al., 2019). PH domain leucine-rich repeat protein phosphatase-1 (PHLPP1) has been located to participate in the regulation of cell survival and cell apoptosis (Aviv and Krishenbaum, 2010). PHLPP1 gene deletion could ameliorate cerebral ischemic injury implying its critical role in neuroprotection (Chen B. et al., 2013). In OGD/ R-treated BMECs, HSYA was located to reverse the increased PHLPP1 evoked by OGD/R and its protective action was abolished as soon as PHLPP1 knockout, which indicated that HSYA attenuated cellular apoptosis following ischemicreperfusion injury in PHLPP1-dependent manner (Cao et al., 2020). A expanding variety of literatures demonstrated that the activation of PI3K/Akt pathway ameliorated I/R-induced apoptosis (Chang et al., 2018; Zhou et al., 2021). Furthermore, glycogen synthase kinase 3 (GSK3), an essential downstream target in the Akt signaling, has been evidenced to regulate key actions involved in intrinsic apoptotic and extrinsic apoptotic pathways (Chen et al., 2014). In MCAO rats, Chen et al. (2013b) provided the constant final results that HSYA inhibited cellular apoptosis following I/R injury by increasing the phosphorylation levels of Akt and GSK3. Moreover, the application of wortmannin, an inhibitor of PI3K, revealed that PI3K/Akt pathway played a good function in HSYA-mediated neuroprotective impact (Chen L. et al., 2013). Altogether, these research demonstrate that HSYA could attenuate apoptosis just after cerebral I/R injury by inhibiting mPTP open through MEK/ERK/ CypD pathway, enhancing mitochondrial function and biogenesis, escalating PHLPP1 level, at the same time as regulating PI3K/Akt/GSK3 pathway.4.six Regulating autophagyAutophagy is really a cellular catabolic course of action that acts as a double-edged sword below pathological situations, contributing to either cell survival or cell damage (MartinetFrontiers in Pharmacologyfrontiersin.orgYu et al.10.3389/fphar.2022.FIGURE 4 HSYA acts around the functional targets and signaling pathways of cerebral I/R injury.Epiregulin Protein custom synthesis Indicator: , upgrade; , downgrade; , undetermined.Galectin-4/LGALS4, Human (His) et al.PMID:23613863 , 2009). It’s commonly agreed that autophagy is closely related with heart illness, cancer and neurodegenerative disease (Martinet et al., 2009). In recent years, expanding proof has revealed that autophagy confers cytoprotection against numerous pathological stresses, including ischemia/ reperfusion injury (Lai et al., 2020). In MCAO rats, Qi et al. (2014) identified that HSYA promoted autophagy within the penumbra via activating AKT-dependent autophagy pathway, which was subsequently verified as a possible mechanism within the HSYAmediated neuroprotection. In contrast, Yang et al. (2018); Zhang et al. (2022) observed that HSYA inhibited autophagy following ischemia for exerting neuroprotection in OGD/R-insulted BMECs and MCAO rats, which can be inconsistent wit.