Phloretin Ameliorates Rheumatoid Arthritis by Suppressing HIF ‐1α‐Dependent Angiogenesis and Modulating of the Autophagy–Apoptosis Balance

Phloretin (PHL) is an effective monomer component of Phellodendri Chinensis Cortex, Spica Prunellae, and fleshy fruits and exerts therapeutic effects on rheumatoid arthritis (RA). However, the underlying mechanism is yet to be elucidated. Following PHL treatment, therapeutic benefits were evaluated in a collagen‐induced arthritis (CIA) rat model using arthritic markers and joint pathology. Network pharmacology, transcriptomics, Western blotting, IHC, molecular docking, Biacore, and cellular thermal shift assay were employed. PHL administration considerably reduced joint swelling, synovial hyperplasia, and bone erosion. Integrated network pharmacology and transcriptomic analyses identified the hypoxia‐inducible factor‐1 alpha (HIF‐1α) axis as a critical target. In vitro experiments indicated that PHL effectively inhibited TNF‐α‐induced fibroblast‐like synoviocyte (FLS) proliferation, migration, invasion, and glycolytic reprogramming, promoted apoptosis, and suppressed excessive autophagy. Furthermore, in a coculture system, PHL substantially attenuated FLS‐induced tube formation in human umbilical vein endothelial cells. Furthermore, PHL demonstrated high affinity for HIF‐1α and accelerated the degradation of HIF‐1α protein. Importantly, HIF‐1α overexpression reversed PHL's inhibitory effect. RA severity was alleviated in Hif1a +/− mice, validating HIF‐1α's pathogenic role in disease progression. PHL exerts anti‐RA effects by targeting HIF‐1α to modulate glycolysis and the autophagy–apoptosis balance in FLS, thereby inhibiting synovial angiogenesis. These findings provide a strong foundation for developing and applying PHL as a potential therapeutic agent for RA.