Bergenin attenuates traumatic brain injury via inhibition of microglial PFKFB3-driven glycolytic-inflammatory crosstalk.

1. Int Immunopharmacol. 2026 Mar 1;172:116181. doi: 10.1016/j.intimp.2026.116181. Epub 2026 Jan 10.

Bergenin attenuates traumatic brain injury via inhibition of microglial PFKFB3-driven glycolytic-inflammatory crosstalk.

Sun B(1), Zhang A(2), Feng S(1), Jamali AW(1), Jia Z(1), Xu Y(1), Wang Z(1), Zhao J(3), Sun G(4), Liu L(5).

Author information: (1)Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China. (2)Department of Neurosurgery, Beijing Tiantan Hospital, National Center for Neurological Disorders, Capital Medical University, Beijing, China. (3)Department of Neurosurgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050000, China. (4)Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China. Electronic address: sungzh705@hebmu.edu.cn. (5)Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China. Electronic address: 27400950@hebmu.edu.cn.

Traumatic brain injury (TBI) initiates a complex cascade of neuroinflammatory and metabolic disturbances that exacerbate neuronal loss and neurological dysfunction. Microglial glycolytic reprogramming, particularly driven by the rate-limiting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), has emerged as a key driver of secondary injury. Bergenin, a naturally occurring C-glycoside with antioxidant and anti-inflammatory activities, has demonstrated multi-organ protective potential, but its underlying mechanisms of immunometabolic regulation in TBI remain unclear. Here, we integrated transcriptomic profiling, weighted gene co-expression network analysis (WGCNA), and multi-database target prediction to identify PFKFB3 as a critical target of Bergenin in TBI. Machine-learning-based screening and molecular docking, dynamics, and surface plasmon resonance (SPR) assays confirmed a direct and stable Bergenin-PFKFB3 interaction (KD = 6.33 μM). In vivo, Bergenin improved neurological recovery in TBI mice, evidenced by reduced neuronal damage, apoptosis, and pro-inflammatory cytokine production (TNF-α, IL-6, and IL-1β). It also downregulated PFKFB3 and its downstream glycolytic enzymes (HK2, PKM2, and LDHA), indicating attenuation of glycolytic activation after injury. Single-cell transcriptomic analysis revealed microglia-enriched PFKFB3 expression associated with inflammatory signaling and altered intercellular communication patterns. In vitro, Bergenin treatment and silencing of PFKFB3 inhibited LPS + IFN-γ-induced microglial activation, reduced glycolytic activity and promoted a phenotypic shift from pro-inflammatory to anti-inflammatory states, with no further enhancement upon their combination. These findings identify PFKFB3 as an immunometabolic regulation hub in TBI and uncover Bergenin as a promising natural compound that directly targets microglial PFKFB3, reprograms immunometabolic pathways, and alleviates post-traumatic neuroinflammation.

Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.

DOI: 10.1016/j.intimp.2026.116181 PMID: 41520557 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.