2. Academic Validation
  3. Amentoflavone as a dual-target inhibitor of IL11 signaling alleviates intervertebral disc fibrosis

Amentoflavone as a dual-target inhibitor of IL11 signaling alleviates intervertebral disc fibrosis

  • Int Immunopharmacol. 2025 Sep 1:165:115450. doi: 10.1016/j.intimp.2025.115450.
Rongsheng Chen 1,  Zhibin Chen 1,  Yiping Chen 1,  Boxuan Xu 1,  Min Su 1,  Weihong Xu 2
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Department of Spine Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Medical University, Fuzhou 350108, China.
  • 2 Department of Orthopedic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Department of Spine Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China; Fujian Medical University, Fuzhou 350108, China. Electronic address: xuweihong815@126.com.
PMID: 40897114 DOI: 10.1016/j.intimp.2025.115450
Abstract

Background: Fibrotic remodeling of the nucleus pulposus (NP) has been increasingly recognized as a key driver of intervertebral disc degeneration (IVDD), highlighting the role of fibroblast-like NP cells and myofibroblasts in excessive Collagen deposition and tissue stiffening. Meanwhile, small-molecule compounds capable of modulating multiple pathological pathways have drawn growing attention in recent research, making them attractive candidates for IVDD treatment.

Methods: We first analyzed the GSE27494 dataset to identify IL11 dysregulation in degenerated human NP tissues and performed KEGG pathway analysis. The expression of IL11 was then validated in human clinical samples and a mouse annulus fibrosus puncture (AFP)-induced IVDD model. In vitro, fibrotic NP cell models were established using bleomycin (BLM), and the effects of IL11 and its downstream signaling were assessed via western blot and immunofluorescence. Molecular docking was used to screen natural compounds targeting IL11RA and IL6ST. The top candidates, including amentoflavone (AMT), were tested in vitro and in vivo for anti-fibrotic efficacy.

Results: IL11 expression was significantly upregulated in both human and murine degenerative discs. IL11 promoted the expression of fibrotic markers (COL1, α-SMA, PDGFR) and inflammatory cytokines (IL1β, IL6) in NP cells. Molecular docking identified AMT as a high-affinity dual-target inhibitor of IL11RA and IL6ST. AMT treatment reduced IL11 expression and downstream fibrosis in vitro, and attenuated IVDD progression, inflammatory cytokine expression, and fibrosis in the mouse model.

Conclusions: IL11 plays a pivotal role in the fibrotic remodeling of NP cells during IVDD. Amentoflavone suppresses IL11-driven fibrosis by targeting both IL11RA and IL6ST, offering a promising therapeutic strategy for IVDD.

Keywords

Amentoflavone; Fibrosis; IL11; Intervertebral disc degeneration.

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