Protein S-palmitoylation is a reversible lipid post-translational modification that dynamically controls protein localization, trafficking, receptor microdomain organization, autophagy and metabolic signalling. In osteoarticular tissues, this modification provides a plausible biochemical mechanism through which osteoclasts, osteoblast-lineage cells, osteocytes, chondrocytes, synoviocytes and skeletal-muscle cells integrate inflammatory, mechanical and metabolic cues. This review synthesizes current evidence linking S-palmitoylation and depalmitoylation to osteoarticular cell signalling and metabolic adaptation. We focus on experimentally supported mechanisms, including ZDHHC-mediated palmitoylation; depalmitoylation by APT, ABHD and PPT enzymes; palmitoylation-sensitive osteoclast differentiation; inflammatory priming of macrophage-derived osteoclast precursors; BMP/SMAD and organelle-contact-site signalling in osteoblast-lineage cells; ZDHHC11-dependent chondrocyte protection; ZDHHC4-mediated palmitoylation of CCDC50 followed by autophagic clearance of MAP2K4/MKK4; inflammasome regulation; CD36-associated lipid uptake; and palmitoylation-dependent transporter localization and turnover. We distinguish direct skeletal and joint evidence from mechanistic analogues derived from immune, neural, metabolic and cancer systems. We also clarify the distinction between reversible cysteine S-palmitoylation, broader S-acylation and other lipid modifications. Major barriers include incomplete definition of enzyme and substrate relationships, false-positive risk in palmitoyl-proteomic workflows, limited temporal resolution, insufficient validation in primary human tissues, uncertain tissue specificity and the off-target effects of non-selective palmitoylation inhibitors. A cell-biochemistry-centred view of the dynamic balance between palmitoylation and depalmitoylation may clarify how lipid modification regulates osteoarticular cell function and may help prioritize experimentally testable, substrate-specific mechanisms for future validation in osteoarthritis, osteoporosis and inflammatory joint disease.

Qi Huang Granules (QHG), a traditional Chinese medicine (TCM) formulation, have been applied clinically for over two decades to treat dry age-related macular degeneration (AMD) and associated fundus lesions. Although its retinoprotective effects have been documented, the associated underlying mechanisms are largely unexplored. The present work focused on investigating the therapeutic efficacy of QHG in sodium iodate (NaIO₃)-induced retinal damage, with a particular focus on how the formula regulated the interaction between inflammatory responses and imbalances in mitochondrial dynamics. UPLC-HRMS, network pharmacology, and molecular docking analyses were integrated for identifying mitochondria-associated bioactive constituents and potential targets of QHG. In the experimental model, retinal injury was induced in rats through tail vein injection of NaIO3. Retinal morphological and ultrastructural changes were assessed by HE staining and transmission electron microscopy. To assess mitochondrial function, mitochondrial membrane potential, mtROS levels, and mtDNA integrity were measured. Additionally, ELISA was performed to quantify IL-1β and IL-18 levels. Key marker levels, including p-DRP1, DRP1, OPA1, MFN2, and NLRP3, were determined by Western blotting, IHC, and qRT-PCR. DNM1L (encoding DRP1) and MFN2 were identified as the primary targets of QHG through UPLC-HRMS and computational analyses. In vivo experimental results showed that treatment with QHG alleviated morphological alterations and ultrastructural damage to the retina and mitochondria in model rats. Furthermore, QHG treatment increased mitochondrial membrane potential, reduced mtROS levels, mitigated mtDNA damage, and reduced IL-1β and IL-18 contents. Mechanistically, QHG downregulated p-DRP1, DRP1, and NLRP3, while upregulating MFN2 and OPA1. Collectively, these findings demonstrate that QHG can ameliorate retinal morphology and ultrastructural damage in mitochondria, such as cellular mitochondria, improve mitochondrial function, and attenuate retinal inflammation, thereby exerting a protective effect against NaIO₃-induced retinal injury. The underlying mechanism may involve the mitochondrial dynamics-NLRP3 pathway.

Hypertension is a major risk factor for cardiovascular disease and alters the mechanical microenvironment of the vascular wall and target organs. Key mechanical disturbances include disturbed shear stress, excessive circumferential stretch, elevated hydrostatic pressure, and increased extracellular matrix stiffness. These forces are sensed by multiple classes of mechanosensors, including mechanosensitive ion channels, integrin-based adhesion complexes, G protein-coupled receptors, primary cilia, baroreceptor afferents, and nuclear mechanosensing structures. Activation of these sensors engages interconnected Ca²⁺-dependent, RhoA/Rho-associated protein kinase, mitogen-activated protein kinase, phosphoinositide 3-kinase/Akt/endothelial nitric oxide synthase, Yes-associated protein/transcriptional coactivator with PDZ-binding motif, redox-sensitive, inflammatory, and mechano-epigenetic pathways. This review summarizes how altered mechanotransduction may contribute to endothelial dysfunction, vascular smooth muscle cell phenotypic switching, vascular remodeling, and cardiac and renal target-organ injury in hypertension. Mechanotransduction is unlikely to represent a universal initiating cause of hypertension. Rather, it should be viewed as a context-dependent set of adaptive and maladaptive responses that varies according to cell type, vascular bed, mechanical stimulus, disease stage, and experimental model. Physiological mechanotransduction helps maintain vascular homeostasis and baroreflex function, whereas sustained pathological loading may amplify oxidative stress, inflammation, fibrosis, and vascular stiffening. However, most direct mechanistic evidence derives from cultured cells and animal models, and human genetic, tissue, biomarker, and interventional data remain limited. Conventional antihypertensive therapy therefore remains the foundation of clinical management, whereas direct targeting of mechanosensors or downstream mechanotransduction pathways remains experimental and requires stronger human validation.

Intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) is a critical contributor to poor neurological outcomes. In this study, we aimed to identify potential small‑molecule therapeutic agents and systematically validate their neuroprotective efficacy. Bioinformatics analysis was performed to screen ICH‑related hub genes, and Connectivity Map (CMap) was used to predict candidate compounds, followed by molecular docking to verify their binding affinity. The therapeutic effect of TPCA‑1 was further evaluated in a mouse ICH model using neurological scoring, cerebral edema assessment, qPCR, Western blot, and ELISA. Bioinformatics analysis indicated that the chemokine signaling pathway is critically involved in ICH pathogenesis. Molecular docking revealed that TPCA‑1 displayed the strongest binding affinity for CXCR4 among all predicted compounds. In vivo, 20mg/kg TPCA‑1 significantly ameliorated neurological deficits and reduced cerebral edema in ICH mice. Mechanistically, TPCA-1 interacted with CXCR4, as supported by molecular docking, MST, and CETSA assays, and suppressed downstream inflammatory signaling involving NF-κB and AP-1, thereby decreasing the production of pro‑inflammatory cytokines including TNF‑α, IL‑1β, and IL‑6. Importantly, Co-treatment with the CXCR4 inhibitor AMD3100 did not produce additional inhibitory effects. Collectively, TPCA‑1 exerts neuroprotective effects against ICH‑induced SBI by targeting CXCR4, which further inhibits the activation of NF‑κB and AP‑1 and ultimately alleviates neuroinflammation.

Novel therapeutic agents are urgently needed since osteosarcoma is a highly aggressive bone tumor primarily affecting children and adolescents that remains poorly responsive to conventional chemotherapy. Persistent aberrant activation of STAT3, particularly via the IL-6/JAK2/STAT3 signaling axis, is frequently observed across multiple malignancies and correlates with poor prognosis, making STAT3 inhibition a compelling therapeutic strategy for osteosarcoma. In this study, we provide the first evidence that Timosaponin A1 (TA1), a naturally occurring saponin isolated from Anemarrhena asphodeloides Bge., suppresses JAK2/STAT3 signaling in osteosarcoma. By inducing cell-cycle arrest and apoptosis, while inhibiting migration and invasion, TA1 markedly reduced the malignant phenotype of osteosarcoma cells. Mechanistically, TA1 directly bound to JAK2, thereby inhibiting STAT3 transcriptional activity and reducing the phosphorylation levels of JAK2 and STAT3. Furthermore, TA1 effectively inhibited IL-6-induced STAT3 phosphorylation and nuclear translocation. Genetic knockdown of STAT3 significantly impaired osteosarcoma cell proliferation and attenuated the inhibitory effects of TA1, supporting a STAT3-dependent mechanism. Finally, an orthotopic tibial osteosarcoma xenograft model in nude mice was used to evaluate the therapeutic potential of TA1 in vivo. Together, our findings demonstrate that TA1 exerts potent antitumor effects by suppressing aberrant STAT3 activation, highlighting its potential as a promising therapeutic candidate for osteosarcoma.

MicroRNAs (miRNAs) are key post-transcriptional regulators that play critical roles in cellular homeostasis and disease progression. Increasing evidence indicates their involvement in cancer-associated metabolic reprogramming, in which tumor cells adapt to hypoxic and acidic microenvironments by altering glycolysis, lipid metabolism, and alternative carbon utilization pathways. Despite extensive studies on individual miRNAs, a comprehensive integration of their roles across metabolic regulation, diagnostic detection, and therapeutic targeting remains limited. This review summarizes the molecular mechanisms by which dysregulated miRNAs orchestrate metabolic pathways in cancer, with a focus on their roles in glycolytic flux, lipid metabolism, and mitochondrial function. In addition, we discuss recent advances in miRNA detection using biosensor-based platforms, including electrochemical, optical, and field-effect transistor systems, enabling sensitive, non-invasive diagnostics. Furthermore, emerging miRNA-based therapeutic strategies are highlighted, emphasizing their potential to modulate cancer metabolism and improve treatment outcomes. Collectively, this review provides an integrated perspective on miRNA-mediated metabolic regulation in cancer and underscores their potential as diagnostic biomarkers and therapeutic targets.

Chloroquine (CQ) is known for anti-inflammatory and autophagy-inhibitory properties; however, its impact on endotoxin-induced macrophage response remains unclear. This study aims to investigate how CQ acts as a signalling modulator in the oxidative stress-autophagy-apoptosis axis in presence of LPS and how the modulation of TLR4 and NLRP3 affects that axis in murine splenic macrophages. The isolated macrophages were pretreated with TLR4 Ab and NLRP3 inhibitor along with CQ for 30 min and further for an additional 60 min after LPS addition. From the in vitro stimulated cells several functional and cellular parameters along with expression of key signalling protein markers were analysed. Result shows that CQ administration in presence of LPS enhances the intracellular ROS which may contribute to alteration of AMPK-ULK1 signalling. The downregulation of pAMPK-pULK1 confirms that CQ + LPS is associated with alterations in upstream autophagy-regulatory signalling markers and consistent with impaired autophagy-associated processing. Additionally, the accumulation of p62 along with LC3-II cautiously acts as a critical indicator of autophagosome degradation inhibition in response to CQ and LPS. The NLRP3 activation, p62 accumulation further corroborate with the Bax and cleaved caspase 3 overexpression in CQ and LPS administered cells which confirm the apoptosis induction. Restoration of pAMPK-pULK1 reduces the mTOR level and restarts the autophagic phenomenon in the case of dual inhibition of TLR4 and NLRP3 in presence of CQ, LPS. The blocking of TLR4 and NLRP3 is able to mitigate the inflammation by restarting the autophagy and limiting apoptosis in murine splenic macrophages.

Diabetes mellitus (DM) is a global health concern characterized by chronic hyperglycemia, which drives severe microvascular and macrovascular complications. The reciprocal interaction between hyperglycemia and reactive oxygen species (ROS)-induced oxidative stress represents a fundamental mechanism in diabetic pathogenesis. As recent studies identify novel intracellular pathways and highlight the critical role of mitochondria, re-examining the interplay between oxidative stress and intracellular organelles is essential. Unlike conventional models that view oxidative stress merely as a passive downstream consequence of cellular damage, this review introduces a distinct, integrative perspective. We reframe the hyperglycemia-oxidative stress axis as a highly coordinated, organelle-driven signaling network that physically bridges metabolic dysfunction with sterile inflammation. By synthesizing classical metabolic shunts (mitochondrial dysfunction, the polyol pathway, advanced glycation end products (AGEs), protein kinase C (PKC) activation, and the hexosamine pathway) with modern inflammatory signaling cascades, we delineate how hyperglycemia amplifies ROS production. This amplification triggers β-cell dysfunction, insulin resistance, and progressive tissue damage, ultimately driving complications such as retinopathy, nephropathy, neuropathy, and cardiovascular disease. Although cellular antioxidant defenses attempt to maintain redox homeostasis, persistent hyperglycemia continuously compromises these protective mechanisms. By systematically evaluating these cellular interactions, this review elucidates the oxidative stress-related pathogenesis of diabetic complications. Ultimately, we revisit the self-perpetuating mechanisms of the hyperglycemia-oxidative stress vicious cycle, offering a structurally unified and highly integrative framework to guide future research.

Fibroblast growth factor (FGF) constitutes a diverse family of signaling proteins involved in cell proliferation, differentiation, angiogenesis, lymphangiogenesis and tissue regeneration. Emerging evidence suggests that FGFs may also play a pivotal role in inflammatory bowel diseases (IBD). IBD, comprising Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic, relapsing inflammation of the intestines, manifested primarily by persistent abdominal pain and severe diarrhea. In IBD, by activating specific fibroblast growth factor receptors (FGFRs), FGFs modulate the immune response, promote mucosal healing, and regulate extracellular matrix (ECM) remodeling, thereby maintaining intestinal barrier integrity. Expression levels of several FGFs, including FGF1, FGF2, FGF7, and FGF10 are upregulated in IBD. These alterations often reflect disease exacerbation and correlate with inflammatory markers, suggesting the potential of FGFs as biomarkers. Furthermore, studies in animal models of various gastrointestinal (GI) tract diseases demonstrate promising possibilities for the use of recombinant FGFs as a novel therapeutic approach to managing gut inflammation.