Pathological cardiac hypertrophy presents a important public health challenge, particularly in aging populations, highlighting the urgent need for novel therapeutic targets. This study investigates the role and molecular mechanisms of OTUD5 in pathological cardiac hypertrophy. OTUD5 expression is greatly increased in cardiomyocytes from hypertrophic hearts. Deleting cardiomyocyte-specific OTUD5 exacerbates myocardial hypertrophy induced by angiotensin II (Ang II) and transverse aortic constriction (TAC). By contrast, targeted overexpression of OTUD5 in cardiomyocytes alleviates Ang II-induced pathological hypertrophy. Mechanistically, we demonstrate that OTUD5 regulates STAT3 activity by removing the K63-linked ubiquitin chain at lysine 283 (K283) on STAT3 through its C224 residue. This process inhibits both phosphorylation and nuclear translocation of STAT3, effectively relieving its transcriptional repression of PGC1α and enhancing mitochondrial function within cardiomyocytes. Our research uncovers a new OTUD5–STAT3–PGC1α axis that modulates mitochondrial bioenergetics, suggesting it as a potential therapeutic target for pathological cardiac hypertrophy. Pathological cardiac hypertrophy, a major contributor to heart failure, poses important public health challenges. This study explores the role of OTUD5, a deubiquitinase, in regulating cardiac hypertrophy through a new mechanism. Researchers developed a cardiomyocyte-specific Otud5-knockout mouse model to investigate its function in pathological myocardial hypertrophy. They found that OTUD5 expression increased in hypertrophic cardiomyocytes, acting as a protective factor. OTUD5 deficiency exacerbated cardiac hypertrophy and dysfunction in mice, whereas its overexpression alleviated these conditions. OTUD5 achieves this by deubiquitinating STAT3 at the K283 site, inhibiting its activation and nuclear translocation, which in turn enhances PGC1α expression and mitochondrial function. These findings highlight the OTUD5–STAT3–PGC1α axis as a potential therapeutic target for heart failure, suggesting that future research can focus on developing OTUD5 modulators to improve cardiac health. "This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author."
Infection is a leading cause of mortality in patients with chronic kidney disease (CKD), in which T cell dysfunction is considered a typical feature. Although platelets are active participants in immune response, their role in regulating T cell function in patients with CKD remains unclear. In this study, we demonstrate that CD8+ T cell senescence may be a major contributor to the immunosuppressed state of patients with CKD, and that platelets derived from patients with CKD can induce premature CD8+ T cell senescence, potentially through mediating mitochondrial dysfunction. Further investigations reveal that platelet-derived microparticles (PMPs) from patients with CKD promote CD8+ T cell senescence via transferring miR-550a-5p, thereby decreasing PMPCB expression and inducing NDUFS8 cleavage failure. Finally, inhibition of miR-550a-5p and pretreatment with nicotinamide mononucleotide are capable of preventing platelet-induced CD8+ T cell senescence in CKD patients. Collectively, these findings suggest that the ectopic transient expression of platelet-derived miR-550a-5p in CD8+ T cells promotes cellular senescence by regulating the PMPCB–NDUFS8 axis, which can be exploited to treat CKD-associated immunosenescence. Chronic kidney disease (CKD) poses a significant global health challenge, with infection being a major cause of morbidity and mortality owing to immune dysfunction. This study reveals that premature senescence of CD8+ T cells is a key feature of immune dysregulation in patients with CKD. Researchers investigated the role of platelets in this process, showing that platelets from patients with CKD release microparticles (PMPs) containing miR-550a-5p, which induce mitochondrial dysfunction and senescence in CD8+ T cells by downregulating PMPCB and affecting the NDUFS8/NAD+ axis. Combining human samples and animal models, the study demonstrated that inhibiting miR-550a-5p or overexpressing PMPCB could mitigate these effects. These findings highlight a novel mechanism of immune dysfunction in CKD and suggest potential therapeutic strategies, such as targeting the PMPCB–NDUFS8 axis or using nicotinamide mononucleotide to prevent CD8+ T cell senescence. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of antiresorptive therapy, yet no reliable circulating biomarker exists for risk stratification. Using an unbiased serum proteomics approach in a multicentre framework, we identified dopamine β-hydroxylase (DBH) as a differentially expressed protein with significantly lower levels in patients with MRONJ. This finding was validated in an independent clinical cohort and further supported in the UK Biobank population. Circulating DBH levels were positively associated with blood-pressure traits, consistent with its role as a surrogate marker of sympathetic nervous system activity, and suggesting that reduced DBH levels in MRONJ may reflect altered sympathetic regulation. In a mouse model, pharmacological sympathetic inhibition with propranolol exacerbated jaw osteonecrosis and further suppressed osteoclast activity in the presence of zoledronic acid. Osteoblast–osteoclast co-culture experiments demonstrated additive inhibitory effects on osteoclast differentiation under β-adrenergic blockade. Together, these findings support an association between reduced circulating DBH levels and MRONJ and suggest that sympathetic dysregulation may contribute to disease pathogenesis. Circulating DBH may serve as a candidate biomarker for risk assessment and disease monitoring in patients receiving antiresorptive therapy. Medication-related osteonecrosis of the jaw (MRONJ) is a serious condition linked to antiresorptive treatments, particularly in cancer patients receiving high-dose bisphosphonates. This study identifies dopamine β-hydroxylase (DBH) as a potential biomarker for MRONJ, addressing the lack of reliable circulating markers for MRONJ. Researchers used high-resolution serum proteomics to analyse samples from MRONJ patients and controls, identifying reduced DBH levels in MRONJ cases. Validation in an independent cohort and UK Biobank data confirmed these findings, showing that lower DBH levels correlate with increased MRONJ risk. The study also explored the role of sympathetic signalling in MRONJ pathogenesis, finding that propranolol, a β-adrenergic blocker, exacerbates MRONJ in a mouse model. These results suggest that DBH could serve as a biomarker for MRONJ and highlight the potential impact of sympathetic regulation on the disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Microglia play a crucial role in maintaining homeostasis of the central nervous system, whereas their dysfunction is implicated in the pathogenesis of various neurological diseases. Nevertheless, interspecific genetic differences pose challenges to translating findings from conventional rodent models. Human pluripotent stem cell-derived microglia offer a genetically relevant alternative, but these cells undergo profound transcriptomic changes and lose key homeostatic features when isolated from physiological brain cues. Accordingly, research has increasingly focused on advanced modelling platforms designed to restore the microenvironment required for in vivo microglial identity and functionality. This review examines the evolution of human microglial platforms, encompassing foundational generation protocols and multicellular integration. The discussion extends from two-dimensional co-cultures to three-dimensional brain organoids and includes human microglia chimeric models established via xenotransplantation to provide a physiological niche. In summary, the human pluripotent stem cell-based approach represents a valuable experimental pipeline for microglia research, facilitating the investigation of polygenic structures underlying human neurological diseases, from high-throughput screening to in vivo preclinical validation. Microglia, the resident immune cells of the central nervous system, play crucial roles in neural development and disease response. Recent studies highlight the limitations of rodent models due to genetic differences, prompting the development of human pluripotent stem cell-derived microglial models. These models, including planar co-cultures, three-dimensional organoids and chimeric brain xenografts, preserve human genetic features and offer controlled environments for research. The review discusses how these platforms advance neuroimmune research and therapeutic assessments. Results show that human pluripotent stem cell-derived microglia maintain homeostatic functions and respond to pathological stimuli, unlike their rodent counterparts. These findings are significant as they provide a more accurate representation of human microglial behaviour in disease contexts. The study advances our understanding of microglial biology and suggests future directions, such as integrating vascular networks and ageing protocols to better model human neurological diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
The efficacy of PET image-guided immune checkpoint inhibitor-based therapy in hepatocellular carcinoma (HCC) management is limited by the lack of direct monitoring of therapeutic response. A key challenge is the mismatch between the therapeutic pathway and the imaging target, which hinders the accurate assessment of treatment outcomes. We addressed this challenge by combining anti-PD-L1 immunotherapy with Olaparib, a strategy that promotes ferroptosis in BRCA wild-type HCC by suppressing SLC7A11, thus allowing for therapeutic response evaluation via [18F]FASu PET imaging of SLC7A11 expression. The combination treatment resulted in a 57% reduction in tumor volume, accompanied by decreased Ki-67 expression and increased levels of γ-H2AX and 8-OHdG. [18F]FASu PET imaging revealed significantly lower SUVmax and tumor-to-background ratios in the combination group, correlating with SLC7A11 downregulation. Mechanistically, GPX4 downregulation, glutathione (GSH) depletion and elevated malondialdehyde (MDA) levels confirmed the activation of ferroptosis. Notably, no therapeutic or imaging response was observed in immunodeficient models. Thus, the SLC7A11-targeted PET tracer [18F]FASu offers a clinically translatable biomarker for monitoring treatment efficacy, establishing a novel theragnostic paradigm that directly evaluates treatment response via PET imaging. Immune checkpoint inhibitor-based combination therapies have improved outcomes in hepatocellular carcinoma, but evaluating treatment response remains challenging because current molecular imaging targets are poorly aligned with therapeutic mechanisms. Here, the authors demonstrate that anti-PD-L1 and the PARP inhibitor Olaparib cooperatively suppress SLC7A11 to induce ferroptosis, enabling direct visualization of therapy-induced molecular changes using SLC7A11-targeted [18F]FASu PET. In mouse models, the combination therapy enhanced antitumor immunity, promoted ferroptosis, and markedly reduced tumor growth, whereas decreased [18F]FASu uptake accurately reflected SLC7A11 downregulation. These findings establish a therapeutic–imaging target-matched strategy that enables mechanism-based monitoring of immunotherapy responses and supports the development of precision imaging biomarkers for hepatocellular carcinoma. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
