Research Square · Oct 19, 2026

Metabolic Reprogramming by Time-Restricted Fasting Attenuates Astrocytic Oxidative Stress and Mitochondrial Apoptosis after Ischemic Stroke via BDH1/SLFN2/NRF2 Axis

By Yin H, Zhang Y, Ci H et al.

Metabolic disturbances in the brain and peripheral tissues after ischemic stroke exacerbate secondary brain injury and impede neurological recovery; however, effective targets and practical strategies for correcting these disturbances remain lacking. By integrating Bulk RNA sequencing, single-nucleus RNA sequencing (snRNA-seq), and Mendelian randomisation analysis, we found that glycolipid metabolism in the nervous system is severely disrupted after stroke, with substantial differences across cell types. We subsequently investigated whether Time-Restricted Fasting (TRF), a dietary regimen known to improve metabolic health, could restore metabolic homeostasis after stroke. TRF significantly alleviated post-stroke metabolic dysregulation and, unexpectedly, increased the production of endogenous ketone bodies and their utilisation in neural tissues. In this response, BDH1, a key enzyme involved in ketone-body utilisation in astrocytes, was linked to post-stroke metabolic imbalance and oxidative stress injury: silencing BDH1 in astrocytes markedly exacerbated post-stroke oxidative stress and mitochondria-dependent apoptosis. We also observed that semaglutide prevented cerebral ischemia-reperfusion injury, an effect that may be attributable to its improvement of glucose homeostasis and enhancement of ketone metabolism.

doi.org/10.21203/rs.3.rs-10716198/v1Open accessInterventions