Pathogenesis of Osteoarthritis: Mechanisms of Action of Disulfidptosis and Targeted Therapeutic Strategies

May 11, 2026Drug design, development and therapy

How Disulfidptosis May Contribute to Osteoarthritis and Possible Targeted Treatments

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Disulfidptosis may play a role in the pathogenesis of osteoarthritis (OA) through the accumulation of disulfide bonds and metabolic disturbances.

Pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6 are associated with cartilage degradation and inflammation in OA.
Disulfidptosis is linked to increased expression of SLC7A11 and depletion of NADPH, resulting in cellular collapse.
Chondrocytes and synovial cells in the OA microenvironment may be more vulnerable to disulfidptosis due to oxidative stress.
This cell death process could contribute to heightened inflammation by releasing damage-associated molecular patterns (DAMPs) and factors related to cellular aging.
Therapeutic strategies targeting disulfidptosis in OA include phytochemicals, traditional Chinese medicines, and specific inhibitors, though current evidence of their efficacy is limited.

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The onset of osteoarthritis (OA) involves the interplay of mechanical stress, inflammatory responses, and metabolic disorders. Pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6, drive cartilage degradation, synovitis, and subchondral bone remodeling through activation of NF-κB and MAPK signaling pathways. Recent studies have identified disulfidptosis, a novel form of programmed cell death, and suggest its potential involvement in OA pathogenesis. This death modality is triggered by abnormal intracellular accumulation of disulfide bonds, dependent on high SLC7A11 expression and NADPH depletion, leading to cytoskeletal protein cross-linking and cellular collapse. In the OA microenvironment, chondrocytes and synovial cells are hypothesized to exhibit increased susceptibility to disulfidptosis owing to metabolic imbalance, impaired glucose uptake, and oxidative stress. This process may not only cause direct loss of cellular function but also potentially amplify inflammatory responses through the release of damage-associated molecular patterns (DAMPs) and senescence-associated secretory phenotype (SASP) factors, thereby theoretically contributing to a vicious cycle of inflammation and M1 macrophage polarization that exacerbates cartilage destruction. Potential therapeutic strategies targeting this pathway include: phytochemicals (eg, curcumin, resveratrol) that modulate redox balance; traditional Chinese medicines (eg, Duhuo Jisheng Decoction) with multi-target anti-inflammatory properties; specific inhibitors such as SLC7A11 antagonists or G6PD activators; hydrogel-based drug delivery systems for localized sustained release; and bone transport technology that activates Piezo1 mechanoreceptors to enhance antioxidant defense. While these approaches represent promising investigational directions, direct evidence validating their efficacy against disulfidptosis in OA remains limited. Future studies must clarify the functional significance of disulfidptosis in OA and rigorously evaluate targeted therapies in preclinical models before clinical translation can be considered.

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Pathogenesis of Osteoarthritis: Mechanisms of Action of Disulfidptosis and Targeted Therapeutic Strategies

Abstract

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