Kaempferol functionally reprograms CD47 signaling to promote cytoprotection and attenuate oxeiptosis in severe acute pancreatitis

  • Phytomedicine. 2026 Jul 25:157:158305. doi: 10.1016/j.phymed.2026.158305.
Yu Tian  1 ,  Yan Zhang  1 ,  Qiang Gao  1 ,  Peng Zhang  2 ,  Lanlan You  3 ,  Rongzhong Huang  4 ,  An Zhang  5 ,  E Wen  6
Affiliations
  • 1. Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2. Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China; Intensive Care Unit, Yubei District Hospital of TCM, Chongqing, China.
  • 3. Department of Ultrasound, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 4. Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 5. Department of Critical Care Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 6. Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 42184499 DOI: 10.1016/j.phymed.2026.158305
Abstract

Background: Severe acute pancreatitis (SAP) lacks targeted therapies, and massive loss of functional pancreatic acinar cells (PAC) drives mortality. Kaempferol (KA) possesses well-established anti-inflammatory and cytoprotective activities and is derived from herbal medicinal Plants, but its direct molecular targets and mechanism of action in SAP remain undefined.

Purpose: To evaluate the protective effects of KA against SAP and to elucidate its molecular mechanism of specific action, with a focus on identifying the direct cellular target through which KA exerts its cytoprotective effects.

Study design: Gain‑/loss‑of‑function in vitro and PAC‑specific CD47 SAP mouse models, combined with multi‑omics screening and biophysical assays.

Methods: CD47 manipulation (siRNA/overexpression) was performed in primary PACs and cell lines, combined with WT/CD47-/-/Mist1‑CD47‑iOE (PAC‑specific) mouse models. Network pharmacology, transcriptomics and proteomics were integrated to screen and validate KA's protective effects. Computational‑experimental approaches (molecular docking/dynamics, CETSA, SPR, co‑IP, pharmacological epistasis) characterized KA's allosteric modulation of CD47 signaling.

Results: CD47 was upregulated in SAP; its knockout reduced PAC death via KEAP1/PGAM5/AIFM1-driven oxeiptosis. KA reduced PAC death across genotypes, afforded no extra benefit in CD47-KO, and was not overridden by CD47‑OE. Mechanistically, KA allosterically binds CD47 ectodomain, stabilizes the CD47‑ UBQLN1 complex, and redirects signaling from Gαi‑mediated death to Gβγ/ ERK/NRF2‑mediated survival. ERK inhibition attenuated KA's protection. KA's action was CD47‑dependent.

Conclusion: This study identifies anti-oxeiptosis as a novel pharmacological activity of KA in SAP. This is achieved through allosteric modulation of CD47, redirecting its signaling from death‑promoting to a protective axis via activating Gβγ/ERK/NRF2 to suppress oxeiptosis. These findings reveal the CD47‑oxeiptosis axis as a therapeutic target and position KA as a promising candidate for SAP therapy, adding a new mechanistic dimension to KA's known pharmacological profile.

Keywords
CD47; G protein signaling; Kaempferol; Oxeiptosis; Severe acute pancreatitis; Ubiquilin-1.
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