Microglial metabolic reprogramming: Aucubin inhibits aldose reductase to reverse diabetic neuropathic pain

This letter critically comments on the article by Zheng <i>et al</i> investigating the role of aucubin in alleviating diabetic neuropathic pain (DNP). DNP arises from hyperglycaemia-induced nerve injury and microglial reprogramming toward aerobic glycolysis. Aldose reductase (also known as AKR1B1) redirects excess glucose flux through the polyol pathway, thus increasing oxidative stress and inflammation. Zheng <i>et al</i> show that aucubin, a plant iridoid glycoside, reverses streptozotocin-induced mechanical and thermal hypersensitivity and anxiety-like behaviour in mice. Mechanistically, aucubin restores microglial morphology, reduces glycolytic flux, enhances oxidative phosphorylation and lowers tumour necrosis factor-α, interleukin (IL)-1β and IL-6 levels in spinal tissue and cultures of the BV-2 microglial cell line. Network pharmacology and molecular docking analyses identify AKR1B1 as a key target, confirmed by the fact that short hairpin RNA knockdown of AKR1B1 eliminates the effects of aucubin. Contrary to the other studies, this study uniquely implicates the polyol pathway in microglial immunometabolism.