Although intracerebral hemorrhage (ICH) associated disability and mortality has decreased due to improvements in clinical management and emerging therapies methods, effective pharmacological therapies to improve neurological outcomes in the late phase of ICH still remain uncertain (Greenberg et al., 2022; Schrag and Kirshner, 2020; Sheth, 2022). Our previous study and other evidences indicate that enhancing intrinsic neurogenesis is a potential better therapeutic intervention for neurological recovery from brain injury (Bai et al., 2022; Liao et al., 2019; Liu et al., 2021). Moreover, these research suggests that stimulating intrinsic neurogenesis to the functional repair of the central nervous system (CNS) has unique and significant advantages: (1) reduce the body's own immune defenses, (2) easy to administer, and (3) precisely affects neural stem cells with less effect on surviving neurons and other cells (Dillen et al., 2020; Wakhloo et al., 2020; Zhou et al., 2018). There is thus a potential value in better therapeutic interventions aimed at supporting the endogenous neurogenic response for neurological recovery from ICH.

Leptin (LEP), a hormone derive from adipose tissue, has recently reported that it has an important role in enhancing neurogenesis (Casado et al., 2023b). Hippocampal LEP enhances neurogenesis and boosts cognition performance in animal models (Yook et al., 2019a). In addition, LEP-based therapeutic treatment for Alzheimer's disease (AD) has been proposed because LEP treatment enhances adult neurogenesis and reduces AD pathological features (Calio et al., 2021). Despite the above-mentioned findings supporting LEP as generally neuroprotective via enhancing endogenous neurogenesis, the underlying mechanisms of LEP's pro-neurogenic effects on ICH has not been fully discussed.

Withaferin A (WFA), a bioactive component of Withania somnifera (L.) Dunal (Solanaceae) (Hassannia et al., 2020). Pharmacological studies on WFA's effects has revealed that it has anti-tumor properties, guards against diabetes, and curbs obesity (Guo et al., 2022; Lee et al., 2021; Tang et al., 2020; Tekula et al., 2018). Our recently study showed that WFA therapy could reduce secondary brain damage brought on by traumatic brain injury by reducing endothelial cell apoptosis and regulating microglia activation (Zhou et al., 2020a). It is noteworthy that we also found that WFA blocks ferroptosis and protects against acute stage of ICH by activating Nrf2/HO-1 pathway (Zhou et al., 2022). Thus, it is suggesting that WFA may have a significant neuroprotective effect in ICH, although the role of WFA in the later stages of ICH remain unclear. Notably, Jaemin Lee have documented that long-term continuous administration of WFA significantly increased the potency of leptin (Lee et al., 2016). Moreover, the correspondences between WFA treatment and LEP effects enlightened us to proposed that if endogenous LEP could be increased with WFA treatment, it would be of significant interest for improvement of neuro-dysfunction followed ICH and neuronal plasticity.

Hence, in this study, we demonstrated that WFA-based therapeutic treatment may provide greater beneficial in enhancing LEP-mediated endogenous neurogenesis for ICH re-repair. Also, the specific mechanism of LEP proneurogenic through upregulation of STAT3/SOCS3 pathway was discussed. These findings could lead to a better understanding of ICH-related events as well as a novel post-ICH cell therapy strategy.