So far, we have no cure for osteoarthritis (OA)—the most common disease of the joints, affecting over 500 million individuals globally, a chronic degenerative joint pathology with a global prevalence of 22.9% in individuals aged 40 and over, characterized by progressive cartilage degradation, synovitis, and subchondral bone remodeling [1–4]. Traditional therapies focus on symptom management, but recent insights into molecular mechanisms—particularly ferroptosis and metabolic reprogramming—have redefined therapeutic strategies [5–9]. This review synthesizes advances in OA pathogenesis, diagnostic innovations, and the multi-target role of CoQ10, emphasizing its potential in precision medicine [10].

Dynamic tissue imbalance and molecular drivers
OA progression involves cross-talk among cartilage, synovium, and subchondral bone [6,11,12]. These cells secrete IL-6 and MMP-13, perpetuating a pro-inflammatory microenvironment [13]. Mechanical stress and its link to ATP synthesis via mitochondrial oxidants in articular cartilage indicates abnormal mechanical stress can impair chondrocyte mechanosensitivity [14]. Furthermore, Ji et al. [15] used single-cell RNA sequencing to uncover the progression of human osteoarthritis and Zhang et al. [16] suggested that reprogramming of the mitochondrial respiratory complex, particularly targeting the SIRT3-COX4I2 axis, might be a strategy to slow OA progression.

Diagnostic innovations
OA diagnostic innovations emerge for early detection. The application of artificial intelligence (AI) to magnetic resonance imaging (MRI) with high-resolution T2 mapping predicts cartilage degeneration years in advance [17]. Additionally, we previously reported that a high-fat diet accelerates osteoarthritis and is associated with a distinct plasma metabolite signature, with AI playing an empowering role in this context [18]. Furthermore, Roemer et al. [19] analyzed the association of knee OA structural phenotypes with progression risk through a secondary analysis from the Foundation for National Institutes of Health Osteoarthritis Biomarkers study (FNIH).

Studies of the ferroptosis-autophagy axis and its core regulatory networks explore the mechanisms and potential therapeutic applications of this axis. Yi et al. [20] investigated novel pH-responsive lipid nanoparticles delivering UA-mediated mitophagy and ferroptosis for osteoarthritis treatment. Jiang et al. [21] reviewed the mechanisms, biology, and role of ferroptosis in disease. Li et al. [22] demonstrated that mitochondria transplantation could transiently rescue cerebellar neurodegeneration by improving mitochondrial function and reducing mitophagy in mice. Chen et al. [23] showed that mitochondrial transplantation could rescue neuronal cells from ferroptosis.

Ferroptosis in OA pathogenesis

Several key molecules, including GPX4 and FSP1, inhibit ferroptosis. Ferroptosis is implicated in various diseases. Recent studies have explored the mechanisms of ferroptosis in disease models including OA, a common joint disorder characterized by cartilage degradation and chondrocyte death, particularly of interest to societies like China with increasing burden of elderly population with OA. Lv et al. [24] used single-cell RNA-seq analysis to identify a ferroptotic chondrocyte cluster and revealed TRPV1 as an anti-ferroptotic target in osteoarthritis. Wang et al. [25] found that mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx. Dixon et al. [5] first introduced the term ferroptosis to describe a novel form of non-apoptotic cell death and identified ferrostatin 1 as the first specific inhibitor of ferroptosis. Doll et al. [26] demonstrated that ACSL4 shapes cellular lipid composition and dictates ferroptosis sensitivity. Ernster & Dallner [27] discussed the biochemical, physiological, and medical aspects of ubiquinone function. Fang et al. [28] provided an overview of the molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease. Lian et al. [29] found that histone H3K27 demethylase UTX compromises articular chondrocyte anabolism and aggravates osteoarthritic degeneration.

Autophagy in OA

Autophagy plays a complex role in osteoarthritis (OA), depending on the stage of disease. In early OA, AMPK/ULK1 activation enhanced autophagic flux, helping clear damaged mitochondria. However, in late OA, overactivation of mTORC1 signaling contributes to disease progression and reduces autophagosome-lysosome fusion efficiency [30]. SIRT1 directly activates autophagy in human chondrocytes [31], while targeting the SIRT3-COX4I2 axis can reprogram mitochondrial respiratory chain complexes and attenuate OA progression [16]. Additionally, autophagy defects may cause cartilage damage during joint aging in mouse models [13]. Recent advances, such as AI-driven drug design and 3D-bioprinted joint models, offer novel solutions for drug screening and therapy development. CoQ10 has its role in mitigating mitochondrial damage through autophagy promotion [23].

Critical interaction nodes

NCOA4-mediated ferritinophagy axis

Interaction nodes in cellular processes regulate iron homeostasis and oxidative stress responses. The selective autophagy receptor NCOA4 coordinates iron homeostasis through ferritinophagy [32], a process that directs ferritin complexes to lysosomal degradation. The NCOA4-mediated ferritinophagy axis plays a key role in directing ferritin complexes to lysosomal degradation, thereby influencing iron levels and contributing to ferroptosis [33]. The p62/SQSTM1-Keap1-Nrf2 axis acts as a molecular rheostat, organizing antioxidant responses to electrophilic stress through phase-separated condensates. Additionally, the HIFs regulatory machinery, particularly HIF-2α, is involved in skeletal growth and osteoarthritis development through transcriptional regulation of endochondral ossification [34]. Mechanistic insights reveal that V-ATPase assembly factor TMEM9B stabilizes V0-V1 domain interactions, with its deficiency leading to lysosomal alkalinization and ferroptosis in renal tubular cells [35]. These findings highlight the complex interplay between autophagy, iron metabolism, and redox signaling in cellular homeostasis and disease.

Mechanisms of action
It possesses antioxidant properties that neutralize lipid peroxyl radicals [36] and enhances mitochondrial optimization by restoring Complex I/III activity and increasing ATP production [37]. CoQ10-loaded nanoparticles have shown efficacy in improving OA by modulating inflammation and mitochondrial dynamics [38]. Additionally, CoQ10 performs epigenetic modulation [23]. Research indicates associations between CoQ10 status, oxidative stress, and muscle strength/endurance in OA patients [38]. CoQ10 also prevents interleukin-1 beta-induced inflammatory responses by inhibiting MAPK signaling pathways in rat articular chondrocytes [10]. Furthermore, Bersuker et al. [39] highlighted the role of CoQ oxidoreductase FSP1 in acting parallel to GPX4 to inhibit ferroptosis.

Synergistic therapeutic strategies
Research explores synergistic therapies combining autophagy-targeted nanoparticles with ferroptosis or apoptosis approaches. Coenzyme Q10 (CoQ10) shows promise when combined with emerging therapies such as Liproxstatin-1, potentially increasing cartilage thickness. Research indicates that PLGA nanoparticles enhance intra-articular CoQ10 retention compared to free drug administration. Na et al. [40] demonstrated that CoQ10 encapsulated in micelles effectively alleviates osteoarthritis by inhibiting inflammatory cell death. These findings align with studies on reactive oxygen species-induced lipid peroxidation mechanisms in apoptosis, autophagy, and ferroptosis [41], further supported by Raizner’s [42] review of CoQ10’s biological functions.

Current limitations and emerging solutions

CoQ10 faces limitations in systemic absorption due to its high lipophilicity, which affects its bioavailability [37]. However, emerging solutions such as 3D-bioprinted joint models offer high-throughput drug screening capabilities, like organ-on-a-chip technology. Additionally, AI-driven drug design has shown promise in identifying FSP1 agonists with high hit rates through virtual screening [43]. Recent advancements also include the development of injectable biomimetic conjugates based on nanoarchitectonics, which show potential for cartilage protection and therapy in degenerative osteoarthritis [44].

The ferroptosis-autophagy axis and metabolic reprogramming emerge as central to OA pathogenesis. CoQ10, with its multi-target actions, represents a promising therapeutic candidate. Future research must address bioavailability challenges and leverage technologies like AI, micro physiological systems, robots, digital-twin and 3D modeling to advance quantitative personalized OA therapies.