Cardiovascular diseases are frequently driven by mitochondrial dysfunction, yet mitochondrial homeostasis extends beyond cell-autonomous quality control to intercellular mitochondrial transfer. Transferred mitochondria can restore bioenergetics and support tissue repair, whereas damaged mitochondrial material can propagate oxidative stress, inflammation and regulate cell death. This duality has limited therapeutic interpretation because mitochondrial transfer is often treated as uniformly beneficial or harmful. This review examines how the identity and functional state of transferred mitochondrial material, donor state, transfer route, recipient metabolism, inflammatory context and intracellular processing shape cardiovascular outcomes. Across major cardiovascular settings, we compare the source and form of the transferred material, the transfer or administration route, recipient responses and the strength of evidence for benefit or harm. These settings include acute ischemia and reperfusion injury, cardiomyopathy, heart failure, vascular dysfunction, pulmonary hypertension, critical illness related myocardial injury and donor heart preservation. Endogenous mitochondrial transfer is considered separately from mitochondrial transplantation, which involves the deliberate administration of isolated mitochondrial preparations. Benefit is most plausible when mitochondria with preserved respiratory function reach salvageable cells within a permissive metabolic window and recipient quality control systems remain functional. Conversely, oxidatively damaged mitochondria, metabolic mismatch or defective clearance can convert transfer into an inflammatory and cytotoxic burden. We therefore frame mitochondrial transfer as a pharmacologically tractable network with distinct intervention nodes, rather than as a single organelle-replacement strategy. Translational opportunities include quality-controlled mitochondrial transplantation, mitochondria-enriched extracellular vesicles, targeted or biomaterial-assisted delivery, selective blockade of pathological transfer and enhancement of macrophage-mediated clearance. Future development should couple product identity, purity, potency and safety testing with mechanism-based patient stratification, recipient-cell tracing and clinically relevant long-term endpoints. This context-guided approach may support precise mitochondria-based therapeutics while defining when mitochondrial supplementation should be promoted, redirected or avoided.
For decades, platinum resistance has remained one of the major barriers to improving outcomes in ovarian cancer. Patients with platinum-resistant ovarian cancer (PROC) generally have shorter overall survival and lower response rates to second-line treatment than those with platinum-sensitive disease. In recent years, innovative therapeutics have emerged for PROC, including antibody-drug conjugates (ADCs), immune checkpoint inhibitors (ICIs), DNA-damage response (DDR) agents, and other rational combination regimens. However, a clinically oriented review integrating the biological basis and clinical applications of these approaches is still lacking. In this review, we summarize the evolving therapeutic landscape of PROC from the following perspectives: (1) the current mechanisms underlying platinum resistance, (2) ADCs targeting FRɑ, HER2, TROP2, CDH6, and other cell surface antigens, (3) immune checkpoint inhibitors and emerging immunotherapy-based combinations, (4) therapeutic strategies targeting the DNA damage repair pathway, (5) anti-angiogenic therapies, and (6) other investigational approaches. We integrate the preclinical and clinical evidence, with particular emphasis on treatment efficacy, patient selection, and targeted biomarkers. By connecting mechanistic insights with clinical development, this review aims to provide a practical framework for treatment decision-making and to identify priorities for future translational research in PROC.
Levodopa (L-DOPA) remains the cornerstone of treatment for the motor symptoms of Parkinson’s disease (PD). However, its long-term use is frequently complicated by levodopa-induced dyskinesia (LID), which substantially limits its clinical benefit. Accumulating evidence suggests that, as nigrostriatal dopaminergic neurons progressively degenerate, serotonergic (5-hydroxytryptamine, 5-HT) neurons increasingly participate in the uptake, conversion, and release of L-DOPA. In the absence of intrinsic dopaminergic feedback regulation, this process may contribute to abnormal fluctuations in striatal dopamine signaling. This review examines the role of the 5-HT system in the pathophysiology of LID, with particular emphasis on how aberrant release of L-DOPA-derived dopamine, impaired spatiotemporal control of neurotransmission, and interactions with glial cells, cholinergic interneurons, and cortico-basal ganglia-related circuits may together amplify dyskinesia-associated maladaptive plasticity. We further summarize therapeutic strategies targeting serotonergic pathways, including 5-HT1A/1B receptor modulation, biased agonism, serotonin transporter-directed interventions, and pharmacological approaches involving other receptor subtypes, and compare their respective strengths and limitations in terms of efficacy, tolerability, and clinical translatability. Finally, we discuss several major challenges in the field, including the discrepancy between preclinical and clinical findings, patient heterogeneity, and the lack of robust biomarkers, and we highlight the need for precision interventions guided by molecular imaging and mechanism-based stratification. Overall, the 5-HT system represents an important entry point for linking the mechanistic basis of LID with therapeutic development, although its translational potential will require more rigorous mechanistic validation and stratified investigation.
Brown adipose tissue (BAT) thermogenesis has emerged as a critical therapeutic target for obesity. However, the precise regulatory mechanisms remain incompletely elucidated. Cold-inducible RNA binding protein (CIRBP) is a stress-responsive molecule involved in the regulation of energy metabolism in various tissues; however, its function in adipose tissue remains unclear. This study aimed to characterize the function and molecular mechanism through which Cirbp regulates BAT thermogenesis. A mouse model with adipose tissue-specific Cirbp knockout (CirbpAdq−/−) was constructed, and obesity and cold exposure models were developed using high-fat diet (HFD) feeding and cold stimulation, respectively. Various methods, including indirect calorimetry, histological analysis, RT‒qPCR, Western blotting, RNA sequencing (RNA-seq), RNA immunoprecipitation combined with sequencing (RIP-seq), and molecular docking, were employed to evaluate how Cirbp affects BAT thermogenesis and systemic energy metabolism. Cirbp expression in BAT was dynamically modulated by cold exposure, with significant upregulation detected upon prolonged stimulation in a tissue-specific manner. Cirbp deficiency in adipose tissue (CirbpAdq−/− mice) markedly reduced both basal and cold-induced systemic energy expenditure, compromised cold tolerance, suppressed BAT thermogenesis, and impaired mitochondrial function. After HFD feeding, CirbpAdq−/− mice displayed significant exacerbation of obesity and metabolic dysfunction, accompanied by a further reduction in BAT thermogenic capacity. In vitro experiments confirmed that Cirbp positively regulates brown adipocyte differentiation and thermogenesis. Mechanistically, integrated RIP-seq and transcriptomic analyses revealed that Vav3 is a direct downstream target of CIRBP in BAT. CIRBP specifically interacts with the 3’ untranslated region (3’UTR) of Vav3 mRNA, thereby increasing the stability of this transcript. Moreover, molecular docking and MD simulations confirmed that CIRBP forms a conformationally stable protein complex with VAV3. Functional rescue experiments demonstrated the essential role of Vav3 in Cirbp-mediated thermogenesis, as Vav3 silencing completely abolished the thermogenic effects induced by Cirbp overexpression. This study identifies Cirbp as a critical positive regulator of BAT thermogenesis, which acts by specifically modulating Vav3 expression. Targeting the Cirbp–Vav3 axis in BAT might be a novel strategy for treating obesity.
Epithelial-mesenchymal transition (EMT) in the amnion of the fetal membranes not only disrupts integrity of the membranes, but also facilitates the production of pro-labor factors, thus participating in the onset of labor. However, the triggering mechanism of EMT in the amnion is not well resolved. Resolution of the mechanism may provide novel therapeutic targets for treatment of preterm birth. Cultured primary human amnion epithelial cells were utilized to investigate the regulation and the role of SOX9 (SRY-box transcription factor 9)/SORBS2 (sorbin and SH3 domain containing 2) axis in EMT in the amnion. A mouse model was used to further study the role of SOX9/SORBS2 axis in parturition. We found that the expression of SOX9 was significantly increased in parturition in human amnion epithelial cells, where SOX9 functioned as a transcription factor driving the expression of SORBS2. Subsequently, SORBS2 prevented the linkage of E-cadherin with cytoskeletal proteins, leading to shedding of the extracellular domain of E-cadherin from the cell membrane, resulting in impairment of E-cadherin-mediated cell adhesion and the occurrence of EMT. Further investigation revealed that transforming growth factor β1 (TGF-β1) was the upstream factor driving SOX9 expression. Studies in pregnant mice demonstrated that intra-amniotic administration of vector expressing Sox9 induced preterm birth along with enhanced EMT in the fetal membranes, and these effects were blocked by shRNA (short hairpin RNA)-mediated knockdown of Sorbs2. These data highlight that activation of the TGF-β1/SOX9/SORBS2 axis drives EMT in the amnion in parturition, and this signaling axis may offer new therapeutic targets to treat both preterm and post-term birth.
