Androgenetic alopecia (AGA) manifests as progressive hair follicle (HF) miniaturization; however, its drivers remain poorly elucidated. Combining spatial and single-cell transcriptomics, we generate a concise single-cell atlas of anagen HFs in male AGA, revealing early changes in cell subpopulations, altered HF stem cell fate determination, and disrupted cell-cell communications. Through ex vivo HF organ culture and humanized mouse models, we demonstrate that hypercontractility of connective tissue sheath (CTS) activates the mechanosensitive channel PIEZO1 in anagen HFs. This mechanotransduction induces ectopic apoptosis of HF progenitor cells and suppresses matrix/ORS cell proliferation, depleting progenitor pools and impairing HF growth, thereby driving progressive miniaturization. Critically, pharmacological inhibition of CTS contraction via ML-7, a selective myosin light chain kinase (MLCK) inhibitor, improves HF growth in both male AGA patient-derived ex vivo models and humanized mice. Our study delineates the cellular dynamics underlying male AGA pathogenesis and identifies mechanopathologically activated CTS as a key driver of HF miniaturization, positioning the peri-follicular CTS as a promising therapeutic target for AGA intervention.

Objective:This study aimed to investigate osteoporosis knowledge (OK) profiles among older women with fragility fractures using latent profile analysis, identify subgroup characteristics, and explore associated factors. Methods:A cross-sectional survey was conducted among 9212 older women with fragility fractures covering 31 provinces in China from September to November 2023. The survey utilized a self-designed general information questionnaire and the Chinese version of the Osteoporosis Knowledge Assessment Tool. Univariate analysis and logistic regression were employed to analyze associated factors. Latent Profile Analysis was applied to classify the older women with fragility fractures based on their OK levels, and multinomial logistic regression was used to identify factors influencing their OK levels. Results:Older women with fragility fractures were classified into five distinct latent profiles according to their OK levels: Low OK group (9.9%), Medium-Low OK group (11.1%), High OK group (50.9%), Medium OK group (18.8%), and High awareness and low management group (9.3%). Key factors influencing the classification of OK levels included marital status, BMI, education level, filial care, postoperative self-care ability, receipt of anti-osteoporosis therapy, use of calcium or vitamin D supplements, perceived necessity of fall prevention, receipt of health education, content of health education, and methods of health education delivery. Conclusion:The OK levels of older women with fragility fractures can be stratified into five distinct profiles. Understanding the heterogeneity of OK levels and its associated factors among this population offers valuable insights for healthcare professionals to formulate targeted interventions. This study makes a significant contribution to the advancement of secondary prevention strategies for osteoporosis.

Non-alcoholic fatty liver disease (NAFLD) and osteoporosis (OP) are two closely linked diseases, with immune cell dysregulation as a pivotal shared cause. However, the key drivers behind their pathogenesis remain poorly understood. Mendelian randomization studies were performed to identify immune-related risk and protective factors for NAFLD and OP, focusing on 731 immune cell traits and 91 circulating inflammatory proteins. Transcriptomic datasets associated with NAFLD and OP were obtained from the Gene Expression Omnibus database, and their consistency and representativeness were assessed through differential gene expression and functional enrichment analyses. ImmuCellAI was then utilized to profile immunocyte abundance and immune-related hub genes were identified via a protein-protein interaction network of common differentially expressed genes in NAFLD and OP. Furthermore, the clinical relevance and main sources of immune-related hub genes were explored using UK Biobank data and single-cell RNA sequencing (scRNA-seq) data. Finally, a high-fat diet (HFD)-induced mouse model was established to validate the bioinformatics findings. We identified 27 and 48 immune phenotypes that had causal effects on NAFLD and OP, respectively, showing similar immunopathogenic backgrounds. Differentially expressed genes maintained high consistency in each disease dataset and were significantly related to disease-specific functions and immune responses, such as inflammation and cytokine signaling. Subsequently, the dysregulation of T-helper (Th) cells was observed in both NAFLD and OP. Notably, three C-X-C motif chemokine ligand (CXCL) family genes, namely CXCL9, CXCL10, and CXCL11, were identified as hub genes, strongly correlating with Th cells. Furthermore, these CXCL family genes showed good diagnostic and predictive efficacy and were mainly expressed in myeloid cells. In the HFD-induced mouse model, the expression levels of these CXCL family hub genes were increased in both livers and bones, alongside elevated proportions of Th1, Th2, and Th17 cells. Our research unveils that the infiltration of immune cells plays a pivotal role in NAFLD and OP, and the interaction between CXCL9/10/11 and Th cells may serve as a shared mechanism underlying the pathogenesis of NAFLD and OP. This finding enhances our understanding of comorbidity mechanisms and presents novel selections for biomarker and therapeutic targets.

Regenerating complex human tissues requires proper cellular assembly and the recapitulation of coordinated functions across multiple biological levels. Organoids, as self-organized three-dimensional cellular structures, provide powerful models for rebuilding organ architecture and studying developmental processes. However, their regenerative potential remains limited by the lack of vascular, neural, and immune integration, which are essential for tissue development, homeostasis, and repair. Recent studies indicate that the progression from tissue-level organization to organ-level coordination and ultimately to system-level functionality depends on dynamic intercellular communication, feedback signaling, and niche interactions. The integration of biochemical, biomechanical, and bioelectrical cues enables multicellular systems to achieve synchronized growth, patterning, and functional adaptation. Complementary bioengineering strategies further guide these intrinsic processes by modulating spatial organization, microenvironmental signals, and intercellular connectivity. This review summarizes emerging methodologies and molecular mechanisms underlying system-level integration in organoids and discusses how these biological processes may bridge the gap between in vitro morphogenesis and in vivo functional regeneration.

Dermal fibroblasts exhibit spatiotemporal heterogeneity, transitioning from coordinating immune signaling and depositing a provisional extracellular matrix during the early inflammatory phase to driving directional migration and mature matrix synthesis in the proliferative phase of wound healing. However, the molecular mechanisms underlying these fibroblast state transitions remain unclear. Here, by integrating single-cell RNA-sequencing, spatial transcriptomics, and in vivo and in vitro analyses in both mouse and skin organoid models for functional validation, we identify a previously underappreciated Gli2-Serpinh1 regulatory axis that plays a key role in fibroblast state transitions during skin wound healing. Serpinh1⁺ fibroblast subsets drive wound closure through re-epithelialization, vascular regeneration, and actin-mediated filopodia formation. Gli2, as a key upstream regulator of Serpinh1, modulates fibroblast function in a level-dependent manner across different healing states. Leveraging organoid technology as a drug discovery platform, we further identify three traditional Chinese medicine candidates that enhance wound healing by activating the Gli2-Serpinh1 axis. Our study reveals the Gli2-Serpinih1 axis as a pivotal regulator of fibroblast state transitions, providing mechanistic insight into fibroblast heterogeneity during wound healing and opening new avenues for precision regenerative therapies.

Symmetry breaking is a fundamental biological principle that converts initially homogeneous systems into spatially and functionally organized structures, forming the basis of tissue complexity. Studying symmetry breaking in skin appendages offers a unique opportunity to understand how fundamental patterning principles operate within a highly accessible and experimentally tractable organ system. In mammals, hair follicles, sweat glands, and sebaceous glands exhibit remarkable diversity in morphology and regenerative capacity, yet all originate from a common epithelial framework through precisely coordinated symmetry-breaking events. Symmetry breaking is governed not only by intrinsic determinants such as morphogen gradients and mechanical forces within tissues, but also by extrinsic cues from the surrounding microenvironment, including extracellular matrix architecture and systemic hormonal or inflammatory signals. These factors interact through mechanisms such as reaction-diffusion dynamics and mechanochemical feedback to direct spatial patterning and cell fate specification. By using skin appendages as a paradigm, this review highlights the central role of symmetry breaking in linking developmental pattern formation, stem cell regulation during regeneration, and structural alterations in disease, offering insights that are broadly applicable across organ systems.

Eccrine sweat glands (ESGs) are critical organs for human thermoregulation, yet their function progressively declines with aging. This study aims to investigate the underlying mechanisms responsible for the age-related impairment of ESG function. Through comparative analysis between skin tissues from young and aged mice/human, we observed structural loosening of aged ESG and a significant reduction in the expression of extracellular matrix (ECM) components—type I and type II collagen. Further investigation revealed a significant upregulation of the inflammatory cytokine interleukin (IL)-1β and matrix metalloproteinases and proteases (MMP)-1 in aged tissues, which can modulate the collagen degradation, suggesting that ECM degradation may be regulated by an inflammatory microenvironment. To validate this hypothesis, we established a model of chronic inflammation by intradermally injecting IL-1β into the footpads of mice. The results demonstrated suppressed ESG function, structural loosening of ESG tissues, and a marked reduction of type I and type II collagen surrounding the ESGs. In summary, this study reveals that type I and type II collagen are distributed around ESGs, providing structural and functional support. The activation of the IL-1β–MMP-1 inflammatory pathway in aging may contribute to ESG dysfunction and structural disruption by degrading the collagen around ESGs.

The mechanisms by which fibroblast-generated biomechanical cues guide tissue regeneration, a process spatiotemporally coordinated by stem cells and their niches, remain largely elusive. Here, using photonic crystal cellular force microscopy (PCCFM), single-cell RNA sequencing (scRNA-seq), in vivo mouse and in vitro skin organoid models, we identify a specific group of dermal fibroblasts surrounding hair follicle stem cells (HFSCs) that creates a biomechanically compliant extracellular matrix (ECM) niche to initiate hair regeneration. We first observed that the matrix stiffness of the dermal niche surrounding HFSCs is markedly decreased during hair regeneration, preceding and facilitating HFSC activation. Reduced matrix stiffness upregulates THBS4 in dermal fibroblasts, which engages integrin β1 to activate EGR1-mediated peroxisomal pathway that drives hair germ cell proliferation. This mechanical adaptation concurrently enhances epidermal-dermal crosstalk, further lowering matrix stiffness and establishing a positive feedback loop that sustains a regeneration-permissive dermal niche. In summary, our findings reveal the mechanical adaptation of the dermal niche and provide a novel mechano-chemical signaling mechanism that coordinates tissue regeneration.

Hair graying is a common feature of physiological aging and is typically evaluated by hair color, melanin content, or melanogenesis-related enzyme activity. However, growing evidence suggests that hair graying results from functional defects at multiple levels of the hair follicle pigmentary unit (HFPU). The HFPU comprises both the intrinsic melanocyte lineage and the extrinsic microenvironment that supports melanocyte function. Here, we review the application of emerging technologies, including organoids, biomaterials, bioprinting, and microphysiological systems, to HFPU reconstruction. Based on the biological functions directly demonstrated by different models, we define six ascending levels of evidence: pigment production, melanocyte differentiation, pigment transfer, progenitor cell maintenance, niche reconstruction, and durable or cycle-like regenerative capacity. Current three-dimensional models reproduce selected structural or cellular components of the HFPU, but remain limited in their ability to sustain melanocyte-lineage renewal, support coordinated pigment transfer, and restore pigmentary function after perturbation. Distinguishing transient hair darkening or short-term melanogenic activation from functional HFPU reconstruction gives a more rigorous evaluation of hair repigmentation models and the interventions tested using these models.

Hair follicle aging is a prominent phenotypic and physiological hallmark of human aging. Recent studies have elucidated the key molecular mechanisms underlying this process, offering a foundation for the development of anti-aging interventions and therapeutic strategies. In this review, we first summarize the phenotypic changes in hair follicles during aging, including hair graying, hair thinning, hair follicle miniaturization, decreased hair follicle stem cell (HFSC) activity, and hair loss. We then review the roles of key cells, such as dermal papilla cells and HFSCs, in the aging process. Next, we explore the molecular mechanisms involved in hair follicle aging, focusing on external factors (e.g., hormonal imbalances and inflammation) and internal factors (e.g., oxidative stress and DNA damage). Finally, we discuss the therapeutic approaches to restore aged hair follicle function and the potential application of emerging technologies (e.g., organoids) to delay aging and promote hair regeneration. This review provides a comprehensive summary of the current research on hair follicle aging, aiming to offer insights for future studies on the underlying mechanisms and potential therapeutic strategies.

Background: Acute mountain sickness (AMS) poses significant health risks for individuals ascending to high altitudes, particularly among volunteers transitioning from low-altitude regions. Early prediction of AMS remains challenging due to the multifactorial nature of its pathophysiology. This study aimed to develop and validate a machine learning-based predictive model for AMS using comprehensive clinical, hematological, biochemical, and echocardiographic parameters. Methods: A prospective observational cohort study was conducted, enrolling 4,636 volunteers from two distinct bases (3,805 for model development and 831 for external validation). Inclusion criteria comprised long-term low-altitude residency and no prior prolonged high-altitude exposure. Exclusion criteria included pre-existing cardiopulmonary diseases and severe systemic illnesses. Least absolute shrinkage and selection operator (LASSO) regression was employed for feature selection, reducing 39 candidate variables to 10 key predictors. Six machine learning algorithms (extreme gradient boosting machine [XGBoost], random forest [RF], artificial neural network [ANN], support vector machine [SVM], logistic regression [LR], decision tree [DT]) were optimized via grid and randomized search with 5-fold cross-validation. Model performance was assessed using the receiver operating characteristic - area under the curve (ROC-AUC), precision-recall analysis, Brier score, and decision curve analysis. An ensemble model was constructed using the top-performing algorithms (XGBoost, RF, SVM). Results: The study cohort demonstrated a 13.2% incidence of AMS (504/3,805 cases) in the model development cohort, with significant physiological differences observed between the affected and unaffected individuals across hematological, hemodynamic, and echocardiographic parameters. Through LASSO regression analysis, ten clinically relevant predictors were identified: age, pulse rate, diastolic blood pressure, prothrombin time, total bilirubin, albumin levels, right ventricular internal diameter, and flow velocities across three cardiac valves (tricuspid, pulmonary, and mitral). Among six evaluated machine learning models, XGBoost, RF and SVM consistently emerged as top performers in both internal and external validation based on comprehensive scoring metrics. The subsequent ensemble model integrating these three algorithms demonstrated exceptional predictive capability, achieving an AUC of 0.864 (95% CI: 0.845-0.883) in internal validation with superior precision (0.857) and optimal calibration (Brier score: 0.159). These strong performance characteristics were maintained in external validation (AUC: 0.822, 95% CI: 0.800-0.843; accuracy: 0.756; Brier score: 0.175), confirming the model’s reliability and generalizability across distinct volunteers. Conclusions: The ensemble machine learning model integrating XGBoost, RF, and SVM outperformed individual algorithms in predicting the risk of AMS risk, offering high accuracy and generalizability. Key predictors included hemodynamic, coagulation, and cardiac functional markers. This tool may enhance pre-deployment risk stratification for volunteers and high-altitude travelers, enabling targeted preventive measures.

Tissue function and homeostasis are sustained through dynamic interactions between resident cells and their surrounding microenvironment. In the skin, these niche-specific signals coordinate epithelial metabolism and secretory activity. Although reduced sweating is a widely recognized phenomena of aging, the cellular and molecular mechanisms underlying eccrine sweat glands decline, particularly those involving age-associated niche remodeling, remain poorly understood. In this study, we combine multiomics profiling with functional assays to define an immune-epithelial circuit that governs sweat gland metabolism and is disrupted during aging. Spatial transcriptomics, single-cell RNA-sequencing, and immunostaining of aged murine paw and human palm skin reveal that structural shrinkage of eccrine sweat glands, elevated senescence-associated secretory phenotype factors, and dendritic cells (DCs) around sweat gland coils (SGCs) were significantly reduced. In youthful skin, DCs support sweat secretion by promoting oxidative phosphorylation SGCs through nicotinamide phosphoribosyltransferase-insulin receptor signaling. However, this signaling axis was perturbed with aging where SGCs secreted macrophage migration inhibitory factor, which signaled through major histocompatibility complex class II invariant chain (CD74) to impair the expression of lysosomal membrane protein and lysosomal protease in DCs through cytochrome b-245 beta chain, exacerbating DC dysfunction and reinforcing a deteriorating glandular niche. Our findings identify DCs as guardians of SGC metabolic homeostasis, revealing a reversible niche-dependent mechanism through DC-SGC crosstalk that drives age-related glandular decline.

The formation of a skin fold named a rete ridge reveals how simple architectural changes reshape tissue mechanics and signalling routes to make a different type of skin structure. The formation of a skin fold named a rete ridge reveals how simple architectural changes reshape tissue mechanics and signalling routes to make a different type of skin structure.

Psoriasis is a common immune-mediated skin disease driven largely by interleukin-17A (IL-17A). Although IL-17A plays a key role in disease pathogenesis, the underlying mechanisms remain incompletely understood. Through bioinformatic analysis, we discovered that proline/arginine-rich end leucine-rich repeat protein (PRELP) expression is upregulated in skin lesions from psoriasis patients following treatment with IL-17A inhibitors (secukinumab, ixekizumab, and brodalumab), despite being significantly downregulated in lesional compared to nonlesional skin at baseline. Experimental assays confirmed that IL-17A suppressed PRELP expression in keratinocytes, consistent with its reduced expression in lesional tissues from both murine models and human patients. Functionally, PRELP suppressed keratinocyte proliferation, promoted apoptosis, and attenuated activation of the NF-κB and MAPK pathways, along with downstream proinflammatory cytokine and chemokine production. By downregulating IL6 in keratinocytes, PRELP further attenuated local IL-17A production via IL6 modulation, suggesting a break in the feed-forward loop of psoriatic inflammation. Intradermal administration of AAV-K14-PRELP ameliorated psoriasis-like findings in mice, including erythema, scaling, epidermal hyperplasia, and Th17 cell infiltration. Mechanistically, IL-17A suppressed PRELP transcription by activating STAT3, which directly binds to the PRELP promoter as a transcriptional repressor. Collectively, our findings identify PRELP as a negative regulator of IL-17A signaling in psoriasis, acting through keratinocyte dysregulation and modulation of Th17 cells. Therapeutic strategies aimed at enhancing PRELP expression may represent a novel approach for treating psoriasis and other Th17-driven inflammatory diseases.

Oxygen availability is a fundamental regulator of tissue homeostasis, yet how tissues adapt to hypoxia during disease progression remains poorly understood. Although psoriasis is mostly characterized as an immune-mediated skin disease, the hallmark hypoxia-related features such as epidermal hyperproliferation and pronounced dermal perivascular recruitment indicate hypoxia importance in psoriasis progression. Here, using spatially resolved hypoxia mapping, multi-omics profiling, transgenic mouse models, psoriatic skin organoids, and functional assays, we identify a dermal hypoxic environment in which perivascular fibroblasts robustly upregulate EPAS1 (encoding HIF2α). These EPAS1 + fibroblasts secrete NAMPT, which activates INSR in vascular endothelial cells that subsequently stimulate epidermal hyperproliferation to drive pathological angiogenesis. Notably, dysregulated blood vessels exhibit impaired retinol transport capacity, compromising keratinocyte differentiation while promoting hypoxic survival. Our findings define an HIF2α–NAMPT signaling axis that spatially segregates hypoxic and metabolic adaptations between dermal and epidermal compartments. This work reframes hypoxia-driven dermal-epidermal crosstalk in psoriasis and provides a conceptual framework for targeting metabolic dysregulation in hypoxia-associated inflammatory diseases.

Purpose: This study aims to establish and validate machine learning-based models to predict death in hospital among critical orthopedic trauma patients with sepsis or respiratory failure. Methods: This study collected 523 patients from the Medical Information Mart for Intensive Care database. All patients were randomly classified into a training cohort and a validation cohort. Six algorithms, including logistic regression (LR), extreme gradient boosting machine (eXGBM), support vector machine (SVM), random forest (RF), neural network (NN), and decision tree (DT), were used to develop and optimize models in the training cohort, and internal validation of these models were conducted in the validation cohort. Based on a comprehensive scoring system, which incorporated 10 evaluation metrics, the optimal model was obtained with the highest scores. An artificial intelligence (AI) application was deployed based on the optimal model in the study. Results: The in-hospital mortality was 19.69%. Among all developed models, the eXGBM had the highest area under the curve (AUC) value (0.951, 95% CI: 0.934-0.967), and it also showed the highest accuracy (0.902), precise (0.893), recall (0.915), and F1 score (0.904). Based on the scoring system, the eXGBM had the highest score of 53, followed by the RF model (43) and the NN model (39). The scores for the LR, SVM, and DT were 22, 36, and 17, respectively. The decision curve analysis confirmed that both the eXGBM and RF models provided substantial clinical net benefits. However, the eXGBM model consistently outperformed the RF model across multiple evaluation metrics, establishing itself as the superior option for predictive modeling in this scenario, with the RF model as a strong secondary choice. The Shapley Additive Explanation analysis revealed that Simplified Acute Physiology Score II, age, respiratory rate, Oxford Acute Severity of Illness Score, and temperature were the most important five features contributing to the outcome. Conclusions: This study develops an artificial intelligence application to predict in-hospital mortality among critical orthopedic trauma patients with sepsis or respiratory failure.

The skin is vulnerable to ultraviolet (UV) exposure, and as a repair mechanism, autophagy activation is essential to eliminate UV‐damaged skin cells to maintain tissue homeostasis. As a UV‐induced protein, heme oxygenase‐1 (HO‐1; 32 kDa) is implicated in protecting cells from oxidative stress and plays an important role in disease prevention. However, the mechanism of photoprotection in skin cells has yet to be fully understood. In the current study, we uncovered that UV radiation induces proteolytic cleavage of HO‐1 into a 26 kDa product that accumulates in the cell nucleus. Biochemical analyses show that caspase‐1 (CASP1) directly binds to HO‐1 and cleaves full‐length HO‐1 at the C terminus. It is further unveiled that the 26 kDa HO‐1 product is a stronger activator of autophagy than full‐length HO‐1, as demonstrated by the activation of autophagy‐related genes. Moreover, the 26 kDa HO‐1 cleavage product promotes translocation of the transcription factor basic helix–loop–helix ARNT‐like protein 1 (Bmal1) into the cell nucleus. This translocation appears to be required for the induction of autophagy, as knocking down Bmal1 fails to activate autophagy induced by the 26 kDa HO‐1 cleavage product. We conclude that a proteolytic cascade involving CASP1/HO‐1/Bmal1 acts to modulate autophagy in UV‐irradiated human skin keratinocytes, presumably as a mechanism to mediate UV photoprotection. Our study identified proteolysis as a regulatory event by generating a previously unknown 26 kDa form of HO‐1 to play a distinct role in the activation of autophagy in UV‐exposed epidermal cells.

Purpose: Coatomer protein complex subunit beta 2 (COPB2) is a crucial component of the coatomer protein complex I, responsible for vesicle transport. Previous studies have indicated that COPB2 is highly expressed in malignant tumors and is involved in cell proliferation and apoptosis. However, the role of COPB2 in osteosarcoma and its underlying mechanisms remain unclear. This study aimed to investigate the impact of COPB2 on proliferation, apoptosis, and colony formation in human osteosarcoma cells, as well as to explore potential mechanisms. Methods: Kaplan-Meier survival analysis was conducted to assess the association between COPB2 expression and the prognosis of osteosarcoma patients using data extracted from the Cancer Genome Atlas (TCGA) database. Additionally, COPB2 expression was examined in osteosarcoma tissue samples and four osteosarcoma cell lines using immunohistochemistry and quantitative real-time PCR (qRT-PCR). COPB2 expression was downregulated using siRNA in U2OS and SAOS-2 human osteosarcoma cells. Cell proliferation and colony formation were assessed using Cellomics/Celigo and Giemsa staining, respectively. Flow cytometry was used to evaluate cell cycle distribution and apoptosis. Tumor growth was evaluated in vivo model. Furthermore, the regulation mechanism of COPB2 on osteosarcoma cells was investigated using the Human Phospho-Kinase Array Kit. Results: Patients with high COPB2 expression exhibited shorter overall survival and disease-free survival compared to those with low COPB2 expression. COPB2 was found to be highly expressed in osteosarcoma tissue samples and cell lines. Silencing of COPB2 significantly inhibited cell proliferation and colony formation. Additionally, COPB2 silencing altered the cell cycle distribution, leading to cell cycle arrest in the G2 phase, and promoted cell apoptosis in osteosarcoma cells. Further investigations revealed that COPB2 silencing inhibited tumor growth and lung metastases of osteosarcoma cells in vivo, and its effects on cell proliferation and apoptosis may be mediated through the regulation of kinase phosphorylation levels. Conclusions: COPB2 expression is increased in osteosarcoma cells and plays a crucial role in cell growth regulation. Silencing of COPB2 inhibits cell proliferation, colony formation, and promotes cell apoptosis. Furthermore, COPB2 silencing inhibits tumor growth in vivo, suggesting its potential as an important therapeutic target in treating osteosarcoma.

Osteoarthritis (OA) is a degenerative joint disorder characterized by complex network dysregulation across the entire joint, which significantly compromises the efficacy of single-target therapeutic interventions. Pathological acidosis and magnesium ion (Mg2+) deficiency have been mechanistically associated with cartilage matrix degradation, abnormal subchondral bone remodeling, and chronic inflammation, collectively driving OA progression. In this study, we engineered porous PLGA microspheres (Cur-Mg/PLGA MPs) incorporating curcumin-modified magnesium hydroxide nanosheets to effectively neutralize excessive hydrogen ions and sustained the release of Mg-Cur nanocomplexes through microporous structures. This acid responsive and neutralization delivery system enhanced the therapeutic capacity of metal-phenolic nanomedicine in suppressing inflammatory responses, inhibiting osteoclast differentiation, and reducing chondrocyte catabolic activity, thereby achieving optimal cartilage preservation. Our in vitro experiments revealed that Cur-Mg/PLGA MPs exhibit remarkable chondroprotective effects under both inflammatory and acidic microenvironmental conditions. Moreover, in vivo evaluations demonstrated that this microsphere system can significantly alleviate OA-associated pain, effectively suppress osteoclast activation, and substantially maintain cartilage matrix homeostasis. Mechanistic investigations identified that Cur-Mg/PLGA MPs inhibit macrophage-to-osteoclast differentiation through ACOD1-mediated mitochondrial metabolic rewiring, ultimately disrupting the “acidosis-osteolysis “vicious cycle in OA pathogenesis. These findings present a novel comprehensive therapeutic strategy for OA management, which has demonstrated significant efficacy in rat models and hold promising potential for clinical translation.