A Randomized Controlled Trial: Efficacy of Wangbi Capsule Plus Conventional Therapy for Knee Osteoarthritis and Its Modulation of the Ferroptosis Pathway.

INTRODUCTION: Knee osteoarthritis (KOA) is a prevalent degenerative disease lacking structural disease-modifying agents. According to TCM theory, its progression involves internal liver-kidney deficiency and external qi/blood stasis with meridian obstruction. We evaluated Wangbi Capsule (WBC) plus diacerein/glucosamine vs. controls (n=180) over 12 weeks. Primary: WOMAC change; secondary: VAS, Lequesne, PhGA, HAQ. In an exploratory subgroup (n=75), PBMC mRNA for GPX4, SLC7A11, ACSL4, plus ESR, hs-CRP, and β-CTX were measured. RESULTS: WBC yielded superior WOMAC reduction (17.77 vs. 22.81, P=0.025), higher excellent response rates, and better all secondary outcomes (P<0.05). hs-CRP fell more with WBC. KOA patients had lower GPX4 and higher ACSL4 vs. healthy controls. Post-treatment, WBC restored both GPX4 and ACSL4 to healthy levels, while controls only reduced ACSL4. In the WBC group, ΔGPX4 and ΔSLC7A11 inversely correlated with ΔESR, Δhs-CRP, and Δβ-CTX (all P<0.01). Safety was comparable. DISCUSSION: These exploratory PBMC mRNA findings suggest WBC may restore systemic redox homeostasis and lipid metabolism via the GPX4/ACSL4 axis, potentially improving the joint's "metabolic-inflammatory" microenvironment. However, these are correlational, not causal, and are limited to mRNA data without protein or functional ferroptosis markers (e.g., MDA, glutathione), absence of joint tissue validation, an open-label design, and a small subgroup size. Furthermore, the lack of P53 changes hints at possible pathways independent of classical P53-mediated ferroptosis, but this remains speculative. Thus, all mechanistic inferences are hypothesis-generating. CONCLUSION: WBC plus conventional therapy improved symptoms safely over 12 weeks; its ferroptosis-related effects await verification in dedicated mechanistic studies.