The role of H۳K۱۸la in regulating CDKN۱B-mediated autophagy in neuropathic pain

Objective(s): To investigate the role of histone lactylation in chronic constriction injury (CCI)-induced neuropathic pain and elucidate its mechanism.Materials and Methods: SD rats were assigned to Normal (n=۶), CCI (n=۲۴), and CCI+oxamate (n=۲۴) groups; the latter two were subdivided into four time points (days ۱, ۴, ۷, ۱۴; n=۶ each). Oxamate (۳۰۰ mg/kg, IP) was given on days ۰, ۲, ۴, ۶, ۱۰, and ۱۲ to inhibit glycolysis. Pain behaviors were assessed. Spinal lactate and histone H۳ lysine ۱۸ lactylation (H۳K۱۸la) were measured. CUT&Tag on day ۱۴ identified CDKN۱B as an H۳K۱۸la target. A separate CDKN۱B siRNA group received intrathecal siRNA on days ۶, ۸, ۱۰, and ۱۲ under oxamate treatment. Spinal IL-۶, TNF-α, IL-۱۰, Beclin-۱, and LC۳-II/LC۳-I ratio were detected.Results: CCI elevated spinal lactate, H۳K۱۸la, and pain, with increased inflammation compared with Normal. Oxamate reduced lactate, global H۳K۱۸la, pain, and inflammation. CUT&Tag showed higher H۳K۱۸la enrichment at the CDKN۱B promoter in the oxamate group, along with up-regulated CDKN۱B, Beclin-۱, and the LC۳-II/I ratio. CDKN۱B knockdown suppressed these autophagy markers and exacerbated pain and inflammation.Conclusion: CCI causes spinal lactate accumulation and global H۳K۱۸la up-regulation, thereby exacerbating pain and inflammation. Oxamate lowers global H۳K۱۸la but specifically increases H۳K۱۸la enrichment at the CDKN۱B promoter, up-regulating CDKN۱B to activate autophagy and alleviate neuropathic pain.

کلیدواژه ها:

Beclin-۱ ، Histone lactylation ، L-lactate ، LC۳ ، Neuroinflammation ، Neuropathic pain