STK40 contributes to neuropathic pain by modulating macrophagic glycogen metabolism and inflammatory responses through the AKT/GSK3β/GYS1 axis

Neuropathic pain (NP) is a complex and debilitating condition characterized by persistent pain due to nerve injury, underscoring the urgent need for improved diagnostic and treatment strategies. Although the glycogen metabolic process (GMP) has been reported to play an important role in NP pathology, the underlying mechanisms remain unclear. We conducted a bioinformatic analysis of transcriptomic datasets of patients with NP in the GEO database and identified three GMP-related hub genes (STK40, PRKAG2, and PHKA1) with strong combined diagnostic potential, achieving an area under the curve (AUC) of 0.832. Subsequent experiments demonstrated that after chronic constriction injury (CCI), only STK40 was significantly upregulated in macrophages of the dorsal root ganglia (DRG). Microinjection-mediated silencing of STK40 in the DRG or conditional knockout of STK40 in DRG macrophages alleviated pain-related behaviors in CCI mice. Mechanistically, STK40 promotes macrophage inflammatory responses by inhibiting the conversion of UDP-glucose (UDPG) to glycogen through the Akt/GSK3β/GYS1 signaling axis. These findings reinforce the importance of GMP in NP and identify STK40 as a potential therapeutic target for NP.