Stein A, Vo S, Freese C
… +6 more, Kluge J, Maus J, Koziollek-Drechsler I, Silva B, Behl C, Clement AM
J Cell Physiol
· 2025 Jul · PMID 40717240
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While Parkinson's disease has a multifactorial etiology, 5%-10% of cases present with identifiable disease-causing gene mutations. Further investigation into these mutations is a way to identify underlying pathologic mec...While Parkinson's disease has a multifactorial etiology, 5%-10% of cases present with identifiable disease-causing gene mutations. Further investigation into these mutations is a way to identify underlying pathologic mechanism. One of the rare Parkinson-associated genes is DNAJC13, coding for an endosome-associated protein. Several lines of evidence suggest that disturbed endosomal pathways are instrumental in the development of Parkinson pathology. Recently, we have shown that DNAJC13/RME-8 is a positive modulator of autophagy, a lysosome-associated degradative process. Here, we further characterize the role of the disease-linked DNAJC13(N855S) mutant and perform biochemical, cell biological, co-localization, and expression analysis by employing a newly established cell line with reduced DNAJC13 expression and by transiently expressing the DNAJC13(N855S) mutant variant. We observed that the DNAJC13(N855S) variant is less stable than the wild-type protein and might thus impact proteostasis. Furthermore, the protein has functional deficits as it cannot compensate for the impaired autophagic activity in cells with chronically reduced DNAJC13 levels. In addition, the DNAJC13(N855S) showed a dominant negative effect on the distribution of the cation-independent mannose-6-phosphate receptor without affecting overall cathepsin D levels or activity. Lastly, we observed a decreased expression of several genes related to autophagy induction and biogenesis in stable DNAJC13 knockdown cells. Our data point toward a loss-of-function mechanism of the DNAJC13(N855S) variant and that chronically reduced DNAJC13 protein levels result in a reduced expression of genes largely involved in endosomal traffic and autophagosome biogenesis. The DNAJC13(N855S) mutant might thus cause disease in part by its instability and in part by a dominant negative effect on the autophagic pathway. These data support a pivotal role of endosomal pathway impairment in Parkinson's disease pathogenesis.
J Cell Physiol
· 2025 Jul · PMID 40696975
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B. Jin, H. Jin, H.-B. Wu, J.-J. Xu, and B. Li, "Long Non-Coding RNA SNHG15 Promotes CDK14 Expression via miR-486 to Accelerate Non-Small Cell Lung Cancer Cells Progression and Metastasis," Journal of Cellular Physiology...B. Jin, H. Jin, H.-B. Wu, J.-J. Xu, and B. Li, "Long Non-Coding RNA SNHG15 Promotes CDK14 Expression via miR-486 to Accelerate Non-Small Cell Lung Cancer Cells Progression and Metastasis," Journal of Cellular Physiology 223, no. 9 (2018): 7164-7172, https://doi.org/10.1002/jcp.26543. The above article, published online on 06 April 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Robert Heath; and Wiley Periodicals LLC. The retraction has been agreed upon following an investigation into concerns raised by a third party regarding unrelated flow cytometry panels in Figure 3a showing implausible similarity. The subsequent investigation by the journal team has identified additional concerns regarding inappropriate duplication of image panels between this article (Figure 2D) and two articles published previously by a different group of authors in an unrelated scientific context, depicting different experimental conditions. Therefore, the editors have lost confidence in the data presented and have decided to retract the article. The authors and their affiliated institution were informed about the concerns and the decision to retract, but they remained unresponsive.
SARS-CoV-2 binds to its obligatory receptor, angiotensin-converting enzyme 2 (ACE2) and capitalizes on decreasing endosomal acidity and cathepsin-mediated spike protein cleavage to enter cells. Endosomal acidification is...SARS-CoV-2 binds to its obligatory receptor, angiotensin-converting enzyme 2 (ACE2) and capitalizes on decreasing endosomal acidity and cathepsin-mediated spike protein cleavage to enter cells. Endosomal acidification is driven by V-ATPase which pumps protons (H) into the lumen. The driving force for H is maintained by the import of chloride (Cl) which is mediated by intracellular CLC transporters. We have recently identified the Proton-Activated Chloride (PAC) channel as a negative regulator of endosomal acidification. PAC responds to low pH and releases Cl from the lumen to prevent endosomal hyperacidification. However, its role in SARS-CoV-2 viral entry remains unexplored. Here, we show that overexpressing the PAC channel in ACE2 expressing HEK 293T cells markedly inhibited SARS-CoV-2 spike-mediated viral entry. Several lines of evidence suggest that this effect was due to the suppression of the endosomal entry pathway. First, the abilities of PAC to regulate endosomal acidification and inhibit pseudoviral entry were both dependent on its endosomal localization and channel activity. Second, the inhibitory effect on viral entry was similar to the suppression mediated by E64-d, a cathepsin inhibitor, while no major additive effect for both treatments was observed. Third, this inhibition was also attenuated in cells expressing TMPRSS2, which provides an alternative entry pathway through the cell surface. Importantly, PAC overexpression also inhibited the number and size of plaques formed by two live SARS-CoV-2 isolates (B.1 and Omicron XBB.1.16) in Vero E6 cells. Altogether, our data indicates that PAC plays a vital role in inhibiting SARS-CoV-2 viral entry and identifies this endosomal channel as a potential novel target against the infection of SARS-CoV-2 and other viruses, which rely on the endosomal pathway.
Obesity arises from a prolonged state of energy intake exceeding energy expenditure, leading to the "whitening" of brown adipose tissue (BAT) and a decline in metabolic function. To investigate factors contributing to BA...Obesity arises from a prolonged state of energy intake exceeding energy expenditure, leading to the "whitening" of brown adipose tissue (BAT) and a decline in metabolic function. To investigate factors contributing to BAT whitening in mice, we used microarray analysis to identify genes differentially expressed in brown adipose-derived stem cells (BADSCs) of wild-type (WT) and ob/ob mice. By intersecting differentially expressed genes between BADSCs and white adipose-derived stem cells (WADSCs) in WT mice, we identified Myl2 as a key gene in BAT function. Myl2 expression showed a 120.8-fold change between ob/ob and WT BADSCs, which was validated by in vivo BAT and in vitro BADSC experiments. Downregulation of Myl2 expression by inhibitor administration significantly reduced the differentiation capacity of BADSCs. Furthermore, overexpression of Myl2 in vitro through adeno-associated virus (AAV) transduction promoted the differentiation of obese mouse-derived BADSCs into brown adipocytes. We further demonstrated the therapeutic potential of Myl2 by administering local injections of Myl2-expressing adeno-associated virus specifically for adipose tissue in ob/ob mice, resulting in improved brown adipose activity and energy metabolism. In summary, this study highlighted the crucial role of Myl2 in BADSC differentiation and BAT function, providing a potential therapeutic target for obesity treatment.
Jeong S, Park S, Lee D
… +4 more, Heo G, Lee Y, Rhee SH, Im E
J Cell Physiol
· 2025 Jul · PMID 40686264
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Damage-associated molecular patterns (DAMPs) are molecules released from damaged or dying cells that contribute to inflammation and cell death. Extracellular ATP, a type of DAMP, has been studied primarily in the context...Damage-associated molecular patterns (DAMPs) are molecules released from damaged or dying cells that contribute to inflammation and cell death. Extracellular ATP, a type of DAMP, has been studied primarily in the context of pyroptosis in monocytes. This study aimed to investigate the role of ATP as a DAMP in mediating pyroptosis within the intestinal mucosal system. Colitis was induced in mice by administering dextran sodium sulfate, followed by analysis of ATP levels and with the expression of pyroptosis-related proteins. Colonic epithelial cells were treated with ATP to assess cell death and pyroptosis levels. Mice with colitis exhibited elevated ATP levels in the colon and serum. Additionally, the expression of pyroptosis-related mediators was significantly upregulated in the colons of these mice. In vitro, ATP treatment increased cell death and mitochondrial dysfunction in colonic epithelial cells. ATP also enhanced inflammatory and pyroptosis responses in these cells, while the expression of apoptosis mediator proteins remained unchanged. Notably, ATP did not further enhance flagellin-induced inflammation. These findings demonstrate that ATP levels are elevated in colitis and that ATP functions as a DAMP to induce pyroptosis in intestinal epithelial cells. This study also highlights a self-propagating cycle where ATP released during pyroptosis triggers further pyroptosis in adjacent cells, exacerbating the condition. Importantly, this study extends our understanding of ATP-mediated pyroptosis to the context of the intestinal mucosal system.
Choi H, Jeong JK, Adasooriya D
… +2 more, Cho SW, Cho ES
J Cell Physiol
· 2025 Jul · PMID 40685976
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Dentinogenesis, the formation of dentin, requires precise coordination of cellular differentiation, extracellular matrix synthesis, and signaling regulation. Here, we elucidate the role of Notum, a secreted Wnt inhibitor...Dentinogenesis, the formation of dentin, requires precise coordination of cellular differentiation, extracellular matrix synthesis, and signaling regulation. Here, we elucidate the role of Notum, a secreted Wnt inhibitor, in orchestrating these processes during dentin formation. In Notum mice, dentin exhibited a thicker yet dysplastic structure with disrupted tubule organization and impaired mineralization, deviating from the functional architecture of healthy dentin. Loss of Notum led to excessive activation of Wnt/β-catenin signaling within the dentin-pulp complex and enhanced expression of odontogenic genes, including dentin sialophosphoprotein (Dspp), and dentin matrix protein 1 (Dmp1). However, this upregulation was uncoupled from proper extracellular matrix composition and mineralization, indicating that initial odontoblast differentiation alone is insufficient for functional dentin formation. At the molecular level, Notum deficiency disrupted matrix integrity, characterized by reduced collagen organization and increased expression of non-collagenous matrix proteins such as bone sialoprotein (Bsp). Collectively, these findings highlight Notum as a critical modulator that fine-tunes Wnt/β-catenin signaling to coordinate cellular differentiation with matrix organization during dentinogenesis. Therapeutic targeting Notum may offer new strategies for restoring dentin integrity and enhancing regenerative outcomes.
Wound healing is a complex, highly orchestrated process involving distinct yet overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Effective healing requires precise cellular and molecular intera...Wound healing is a complex, highly orchestrated process involving distinct yet overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Effective healing requires precise cellular and molecular interactions across these phases, with calcium signaling playing a pivotal role in modulating cellular responses such as migration, proliferation, and differentiation. Among the calcium channels involved, the Transient Receptor Potential Canonical (TRPC) family, particularly TRPC3, emerged as a key modulator of wound repair processes. In this review, we explore the dynamic contributions of TRPC3 to each phase of wound healing, highlighting its regulation of calcium fluxes and the downstream cellular responses critical for effective tissue repair. We will further discuss the altered role of TRPC3 in pathological conditions, such as chronic wounds and diabetic ulcers, where aberrant TRPC3 signaling disrupts normal wound healing, contributing to impaired resolution and fibrosis. By summarizing findings from recent studies, we underscore the potential of targeting TRPC3 as a therapeutic strategy to restore normal wound healing. Finally, we will discuss future directions in TRPC3-targeted interventions, including the development of selective modulators and the use of TRPC3-targeting therapy, to address unmet needs in wound care. This review aims to provide a comprehensive overview of TRPC3's multifaceted role in wound repair and its therapeutic potential in regenerative medicine.
Chatoff A, Kantner DS, Snyder NW
… +1 more, Rink L
J Cell Physiol
· 2025 Jul · PMID 40685935
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Succinate dehydrogenase (SDH) is both Complex II in the electron transport chain (ETC) and a key metabolic enzyme in the tricarboxylic acid cycle. SDH is a heterotetrameric enzyme consisting of four subunits SDHA, SDHB,...Succinate dehydrogenase (SDH) is both Complex II in the electron transport chain (ETC) and a key metabolic enzyme in the tricarboxylic acid cycle. SDH is a heterotetrameric enzyme consisting of four subunits SDHA, SDHB, SDHC, and SDHD, all encoded in the nuclear genome. In addition, the SDH complex requires two assembly factors, SDHAF1 and SDHAF2, which are required for assembly of SDHA and SDHB onto the inner mitochondrial-embedded subunits SDHC and SDHD. Once assembled, SDH catalyzes the conversion of succinate to fumarate coupled to the reduction of ubiquinone to ubiquinol via FAD/FADH and ultimately the generation of ATP via ATP synthase through a functioning ETC. Given the unique dual metabolic role of SDH, loss of activity results in major metabolic rewiring, potentially uncovering metabolic vulnerabilities that could be targeted for pharmacological manipulation in disease states. SDH is a tumor suppressor and SDH-loss is a driver of oncogenesis for cancers including pheochromocytomas, paragangliomas, gastrointestinal stromal tumors, and clear cell renal cell carcinomas. SDH deficiency also plays a role in the pathogenesis in non-neoplastic diseases, including Leigh syndrome and other neurometabolic disorders. Considering the implications of SDH function in both normal physiology and disease, understanding SDH function has fundamental and translational implications. This review seeks to summarize SDH deficiency, focusing on the role SDH plays in metabolism, the metabolic consequences of SDH deficiency, the proteomic consequences of SDH loss, thereby highlight potential therapeutic vulnerabilities in SDH-deficient cells.
Ingraham CH, Villanueva DP, Macaluso A
… +10 more, Tramuta A, Vittori C, Hunter JJ, Rak M, Claudio PP, Ibrahim MA, Del Valle L, Peruzzi F, Jursic BS, Reiss K
J Cell Physiol
· 2025 Jul · PMID 40665659
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We attempt to address two key therapeutic obstacles affecting glioblastoma patients: low ability of anticancer drugs to penetrate the blood-brain barrier (BBB), and temozolomide (TMZ) resistance, by targeting mitochondri...We attempt to address two key therapeutic obstacles affecting glioblastoma patients: low ability of anticancer drugs to penetrate the blood-brain barrier (BBB), and temozolomide (TMZ) resistance, by targeting mitochondrial respiration of glioblastoma cells. We designed and tested over 100 new compounds based on the chemical structure of fenofibrate (FF), which in its prodrug form is cytotoxic to cancer cells by causing severe impairment of mitochondrial respiration. The compounds were designed using two key predictive tools: central nervous system-multiparameter optimization (CNS-MPO) and BBB_SCORE. These algorithms assess how effectively compounds can penetrate the BBB. We initially selected PP1 as a lead compound by testing its BBB penetration, metabolic performance, and antitumoral efficacy. PP1 accumulated in brain tumors and triggered glioblastoma cell death. However, PP1-induced inhibition of mitochondrial respiration was followed by an immediate glycolytic response, which attenuated PP1 toxicity in a glucose-dependent manner. To bypass this limitation, we tested two strategies: (1) the use of PP1 in combination with glycolysis inhibitors; and (2) introduction of a new compound, PP211, which inhibited mitochondrial respiration in the absence of a concomitant increase of glycolysis. Although the combination of PP1 with glycolysis inhibitors was very effective in vitro, this drug combination demonstrated elevated toxicity in mice. PP211, instead, attenuated TMZ-resistant tumor growth and prolonged mouse survival with only minimal general animal toxicity. In summary, we developed and tested a novel mitochondria-targeting drug candidate, PP211, which effectively crosses the BBB, overcomes TMZ resistance, and induces tumor cell death independently of glucose levels-while exhibiting minimal systemic toxicity in preclinical models. These findings support further development of PP211 for glioblastoma therapy.
Heredero-Jiménez S, Martín-Guerrero E, Pizarro-Gómez J
… +5 more, Tirado-Cabrera I, Álvarez-Carrión L, Bellido T, Gortázar AR, Ardura JA
J Cell Physiol
· 2025 Jul · PMID 40665637
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Caveolin-1 (Cav1), a protein present in lipid raft invaginations known as caveolae, regulates the trafficking and signaling of some cell surface receptors. Current evidence suggests that the number of caveolae might incr...Caveolin-1 (Cav1), a protein present in lipid raft invaginations known as caveolae, regulates the trafficking and signaling of some cell surface receptors. Current evidence suggests that the number of caveolae might increase with aging. The parathyroid hormone (PTH) receptor type 1 (PTH1R) regulates osteoblast and osteocyte actions after activation by PTH and PTH-related protein (PTHrP) peptides. PTH1R activation leads to defined biological effects depending on its association with different membrane or intracellular molecules. Since PTH1R exhibits a potential Cav1 binding domain, we hypothesized that PTH1R responses are regulated by Cav1 in cells of the osteoblastic lineage, conditioning PTHrP actions during aging. We report that Cav1 colocalizes with PTH1R at membrane microdomains in osteoblastic and osteocytic cells. Cav1 overexpression modifies PTHrP-dependent signaling in osteoblastic cells by decreasing intracellular calcium accumulation and increasing cAMP levels leading to upregulation of Runx2, osteocalcin, bone alkaline phosphatase, and OPG in a rapid and transient manner. Conversely, Cav1 silencing causes over-phosphorylation of ERK1/2 kinase and overproduction of calcium, which leads to reduced expression of Runx2, osteocalcin, and alkaline phosphatase. Further, the gene expression of Cav1 increases with age in murine bone in vivo and negatively correlates with that of Runx2, osteocalcin and alkaline phosphatase. Moreover, age-dependent overexpression of Cav-1 and caveolae disruption is associated with alterations in PTHrP-dependent bone gene expression in ex vivo cultured bones. FRAP analysis revealed that Cav1 causes PTH1R temporary retention at Cav1 microdomains upon receptor activation, delaying PTH1R internalization. We conclude that PTH1R signaling and PTHrP actions in bone cells are regulated by Cav1 and that Cav1 overexpression with age conditions PTH1R responses in bone.
As an anthracycline chemotherapy drug, doxorubicin (Dox) is generally prescribed to treat a variety of malignant tumors. Nevertheless, Dox exhibited toxicity at a high dosage, which might eventually lead to injury of the...As an anthracycline chemotherapy drug, doxorubicin (Dox) is generally prescribed to treat a variety of malignant tumors. Nevertheless, Dox exhibited toxicity at a high dosage, which might eventually lead to injury of the body. Mitochondrial dynamics, including mitochondrial fission and fusion, regulates mitochondrial homeostasis and cellular function. Mounting evidence has demonstrated that imbalance in mitochondrial dynamics, manifested by increased mitochondrial fission or decreased mitochondrial fusion, is associated with the development of Dox-induced diseases. In this paper, we will elaborate the role of mitochondrial dynamics in Dox-induced diseases, and discuss the regulatory mechanism of mitochondrial dynamics in Dox-induced diseases, including apoptosis, fibrosis, myocardial atrophy and inflammation. Elucidating these issues may provide important value in the diagnosis and potential therapeutic strategies for Dox-induced diseases through regulation of mitochondria dynamics.
Products encoded by approximately 30% of the mammalian genome exit the endoplasmic reticulum via the coat complex II (COPII) system en route to their functional destination. Among these cargoes, APOB-containing lipoprote...Products encoded by approximately 30% of the mammalian genome exit the endoplasmic reticulum via the coat complex II (COPII) system en route to their functional destination. Among these cargoes, APOB-containing lipoproteins stand out as abundant and bulky secretory particles with profound implications for human health and diseases. Recent insights into the specialized intracellular itinerary of lipoprotein metabolism and transport not only shed light on longstanding questions of lipid dynamics, but also highlight challenges faced by the COPII machinery in accommodating these complex, unconventional cargoes. Emerging evidence supports that tightly-regulated COPII condensation enables maximal capacity of cargo transport, providing a potential solution tailored for efficient lipoprotein delivery without affecting general protein secretion. This distinction suggests that targeting COPII condensation may provide new therapeutic strategies for lipid-associated diseases. Indeed, recent studies have identified manganese as a key modulator of this process, offering novel insights into its physiological relevance and potential translations.
Sodium/glucose cotransporter 2 inhibitors (SGLT2i) protect against heart failure and fibroinflammation with an unclear mechanistic. Recombinant interleukin-11 (IL11) therapy for thrombocytopenia induces heart failure sym...Sodium/glucose cotransporter 2 inhibitors (SGLT2i) protect against heart failure and fibroinflammation with an unclear mechanistic. Recombinant interleukin-11 (IL11) therapy for thrombocytopenia induces heart failure symptoms and signs. Profibrotic IL11 upregulates extracellular matrix (ECM) proteins, whereas pro-inflammatory tenascin-C (TNC) is an ECM-derived alarmin. We hypothesized IL11 upregulated TNC to induce fibroinflammation via Toll-like receptor 4 (TLR4) and prototype SGLT2i dapagliflozin counteracted the effects. We stimulated fibroblasts with IL11 and confirmed TNC upregulation. NADPH oxidase 2 (NOX2) is known to participate in TNC-TLR4 signaling. We treated IL11-stimulated fibroblasts with inhibitors of TLR4 (TLR4i) and NOX2 (NOX2i) and found IL11 induced an imperative profibrotic TNC-TLR4-NOX2 auto-amplification loop. IL11 is known to induce ERK-dependent positive autofeedback. By finding TLR4i and NOX2i inhibited IL11-induced ERK phosphorylation, we suspected IL11-ERK joined TNC-TLR4-NOX2 auto-amplification fibroinflammatory pathway. We stimulated fibroblasts with TNC and found IL11 upregulation. We treated TNC-stimulated fibroblasts with TLR4i, NOX2i, or neutralizing IL11 antibody and confirmed TLR4-NOX2 and IL11 were indispensable for TNC-induced fibrosis. We concluded that IL11-ERK, TNC-TLR4, and NOX2 are interdependent in fibroblasts and together make a positive-feedback loop to sustain fibroinflammation. We checked mRNA expression of relevant proteins from proteinatlas.org and found fibroblasts are overwhelming producers of IL11 and TNC in the heart. IL11 receptor subunit alpha (IL11RA) and TLR4 are highly differentially expressed with the former on cardiomyocytes and the latter on macrophages. We therefore proposed a model of differentially activated IL11RA and TLR4 signaling in response to mutually reinforcing IL11-TNC alarmins, to explain how activated fibroblasts pivotally support fibroinflammatory microenvironment and how danger signals induce cell-type-specific responses. Next, we showed dapagliflozin prevented fibroinflammation induced by IL11 or TNC. Mechanistically, we showed dapagliflozin antagonized IL11RA by molecular docking, fluorescence quenching, and grading-dose IL11-signaling inhibitor cocktails studies. In conclusion, dapagliflozin interrupts pro-fibroinflammatory IL11-TNC bi-alarmin mutual reinforcement in human cardiac fibroblasts by antagonizing IL11RA.
Cruz JMC, Yeung H, Alzalzalee R
… +6 more, Yang Q, Kabir H, McDonough SA, Mei X, Conboy MJ, Conboy IM
J Cell Physiol
· 2025 Jun · PMID 40536399
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Exercise and diet are the best-known methods for attenuating aging-related health decline. However, exercise in older age has diminished gains of strength and agility, and a danger of unrepaired muscle damage. Improving...Exercise and diet are the best-known methods for attenuating aging-related health decline. However, exercise in older age has diminished gains of strength and agility, and a danger of unrepaired muscle damage. Improving the understanding of age-related differences in response to exercise, our results demonstrate that in old mice, downhill treadmill (eccentric) exercise causes increased influx of CD45+ cells (inflammation) and fibrotic index (fibrosis) in the heart and skeletal muscles. To explain these changes, we identified newly synthesized proteins through bio-orthogonal noncanonical amino acid tagging (BONCAT) and established that exercise exacerbated age-associated protein patterns through a dysregulated transforming growth factor (TGF)-β, Ras/MAPK/PI3Akt, and JAK/STAT pathways. Testing causality, we found that an inhibitor of TGF-β (Alk5 inhibitor, A5i) in combination with the age-diminished peptide oxytocin, previously shown to rejuvenate muscle and brain in sedentary animals, allowed aged mice to exercise without pathologies of skeletal and heart muscles and youthfully restored their de novo proteomes.
Osteoarthritis (OA) is increasingly recognized as a chronic inflammatory degenerative joint disease. Recent evidence exhibits a higher prevalence of OA among patients with type II diabetes mellitus (T2DM). Metallothionei...Osteoarthritis (OA) is increasingly recognized as a chronic inflammatory degenerative joint disease. Recent evidence exhibits a higher prevalence of OA among patients with type II diabetes mellitus (T2DM). Metallothioneins (MTs) are important proteins involved in controlling physiology and pathophysiology. MT-1/MT-2 have been further found their positive correlation with OA progression, but their precise roles need more examination. This study aimed to investigate the role of MT-1/MT-2 in the development of diabetic OA and the underlying mechanisms. Cartilage was collected from patients with OA-only and T2DM-OA, and from rats classified as healthy, T2DM, and T2DM with destabilization of medial meniscus (DMM) surgery. Additionally, a cell model treated with high glucose (HG) or advanced glycation end products (AGEs) was used to investigate underlying mechanisms. Our results revealed that MT-1/MT-2 levels were elevated in cartilage from T2DM-OA patients and rats, as well as in T2DM rats subjected to DMM surgery. Similarly, primary chondrocytes treated with HG and AGE showed increased expression of MT-1/MT-2, with distinct distributions and regulatory mechanisms: (a) MT-1 enhanced MMP and transcription factor activity without affecting their expressions, whereas MT-2 increased both the activity and expression of MMPs and transcription factors; (b) MT-1 reduced IL6/IL8 expression, while MT-2 promoted it. Furthermore, this differential regulation appears to be mediated by BMP2 autocrine stimulation. These findings underscore the dual role of MT-1/MT-2 in simultaneously activating self-repair and degenerative processes, potentially influencing diabetic cartilage pathogenesis. Our study suggests that MT-1/MT-2 may serve as valuable theranostic targets for diabetic OA in future clinical applications.