Sontidejkul S.Phuengmaung P.Saisorn W.Kaewduangduen W.Doi K.Boonmee A.Benjaskulluecha S.Palaga T.Leelahavanichkul A.Mahidol University2025-08-172025-08-172025-12-01Inflammation Research Vol.74 No.1 (2025)10233830https://repository.li.mahidol.ac.th/handle/123456789/111710Background: Fibroblast growth factor 21 is a molecule responsible for cell energy regulation, mainly produced from hepatocytes, while O6-methylguanine-DNA methyltransferase is a mandatory enzyme for DNA repair. Methods: Because tumors in the livers might enhance hepatocytic FGF-21 production for supporting tumor-associated macrophages (TAM) to promote cancers, the intrahepatic tumor injection model was performed. Results: Indeed, intrahepatic injection of MC38 cells in wild-type mice increased FGF-21 in serum and liver tissue. Murine hepatocytes excreted FGF-21 after induction by cell stresses, lipopolysaccharide, and MC38 supernatant, while human hepatocytes (HepG2) produced FGF-21 after incubation with the conditioned media of CaCO<inf>2</inf>, but neither HK2 nor H292. Intrahepatic MC38 injection in mgmt null mice demonstrated a lower tumor size and intratumoral TAM (CD206-positive cells) but higher FGF-21 production when compared with intrahepatic tumors in mgmt control. Additionally, MC38 supernatant induced M2-like polarization, which was enhanced by recombinant FGF-21. Furthermore, TAM induction by MC38 supernatant caused cell stresses only in mgmt null macrophages but not in mgmt control cells, as indicated by increased cell-free DNA and malondialdehyde with reduced maximal respiration. The TAM transformation-induced cell injury was neutralized by recombinant FGF-21. Conclusion: TAM transformation in mgmt null macrophages induced more severe cell injuries than mgmt control macrophages, leading to the less abundant intratumoral TAM and increased FGF-21 to attenuate the injuries in mgmt null mice with tumors. Further studies on FGF-21 and MGMT in cancers are interesting.Pharmacology, Toxicology and PharmaceuticsImmunology and MicrobiologyArticleSCOPUS10.1007/s00011-025-02077-62-s2.0-1050129270491420908X