Immunometabolic Landscapes of Chronic Pathology: A Comparative Review of Macrophage Plasticity, Ferroptosis, and Therapeutic Interventions in Triple-Negative Breast Cancer and Osteoarthritis

Abstract

Background: Triple-Negative Breast Cancer (TNBC) and Osteoarthritis (OA) represent two distinct poles of chronic pathology: one a highly aggressive, metastatic malignancy and the other a chronic, debilitating degenerative condition. Despite their clinical differences, both are driven by profound dysregulation in the local microenvironment, characterized by aberrant macrophage polarization, metabolic stress, and inflammatory signaling.

Methods: This review synthesizes recent literature to map the molecular intersections between TNBC progression and OA pathogenesis. We analyzed mechanisms of chemoresistance in TNBC, specifically focusing on the VCP-TMEM63A-DERL1 axis and ferroptosis, and contrasted these with synovial inflammation and matrix metalloproteinase (MMP) activity in OA. Furthermore, we evaluated the therapeutic efficacy of soybean-derived bioactive peptides and saponins across these conditions.

Results: Analysis reveals that macrophage plasticity is a critical driver in both diseases. In TNBC, HLF-mediated regulation of ferroptosis and tumor-macrophage crosstalk facilitates progression, while in OA, macrophage polarization drives synovial fibrosis and cartilage degradation. Crucially, soybean bioactives, including genistein and Bowman-Birk inhibitors, demonstrate significant potential in modulating these pathways by suppressing pro-inflammatory mediators (IL-6, NF-kappaB) and regulating autophagy.

Conclusion: There is a remarkable convergence in the signaling nodes governing TNBC and OA. Targeting the inflammatory microenvironment through metabolic modulation—specifically via ferroptosis induction in cancer and inflammatory suppression in arthritis—offers a promising therapeutic avenue. Natural bioactive compounds warrant further investigation as potent, pleiotropic agents capable of addressing these shared molecular targets.

Keywords:

Rheumatoid Arthritis (RA), VAS — visual analog scale, disease-modifying antirheumatic drugs (DMARDs), Annexin A1 (ANXA1), interleukin-6 (IL-6), Disease Activity Score in 28 Joints (DAS28)

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