SIRT1: An Emerging Role in Regulated Cell Death in Ischemic Stroke

Ischemic stroke (IS) globally threatens human health due to its limited treatment options and the severity of its complications, which often result in long-term disability. SIRT1, a key member of the sirtuin family, plays a pivotal role in regulating various cellular processes by facilitating the deacetylation of both histone and non-histone substrates. As a critical regulator, SIRT1 is involved in multiple pathophysiological processes, including neuroinflammation, regulated cell death (RCD), oxidative stress, and more, which are central to the progression of IS. In IS, SIRT1 exerts its effects through a variety of specific mechanisms, including promoting NF-κB and FoxO deacetylation, enhancing eNOS expression, inhibiting NOX production, and suppressing the TLR and NLRP3 inflammasome pathways, which contribute to the regulation of RCD. These actions influence various forms of cell death, such as apoptosis, ferroptosis, pyroptosis, autophagic-dependent cell death, necroptosis, and cuproptosis. Additionally, SIRT1 may function upstream of the RIPK1/RIPK3/ MLKL pathway, thereby contributing to necroptosis activation. Moreover, SIRT1 modulators, including resveratrol, SRT1720, EX-527, and Sirtinol, have demonstrated neuroprotective effects in preclinical and clinical trials. However, challenges such as blood-brain barrier (BBB) permeability, drug stability, and target specificity need to be addressed. Thus, future research should aim to overcome these obstacles and develop novel SIRT1 modulators with better clinical translation potential, ultimately improving IS treatment outcomes. This review further explores the therapeutic implications of SIRT1 modulation in IS treatment and highlights the urgent need for more clinical validation to support its broader application.