搜索结果：BioFactors (Oxford, England)

Glioma, a highly aggressive brain cancer, thrives in an immunosuppressive tumor microenvironment (TME). The Unfolded Protein Response (UPR) is a key adaptive stress pathway implicated in therapy resistance. To discover clinically actionable biomarkers, we employed an integrated multi-omics strategy, combining single-cell and bulk transcriptomic data from multiple glioma cohorts. Using hdWGCNA network analysis, we identified a UPR-associated gene module that defined two molecular subtypes with stark survival differences. Through a rigorous machine learning pipeline (Random Survival Forest, LASSO, and CoxBoost), ANXA5 emerged as the central prognostic gene. High ANXA5 expression consistently predicted poorer overall survival across eight independent datasets, validating its robust prognostic value. Functionally, ANXA5 was linked to extracellular matrix remodeling and immune modulation. Multi-omics profiling revealed that ANXA5-high gliomas exhibit a T-cell-inflamed yet immunosuppressive TME, characterized by elevated immune checkpoint expression. Crucially, ANXA5 demonstrated strong predictive power for response to immune checkpoint blockade (ICB), showing significant correlation with nine established immunotherapy response signatures and accurately discriminating responders from non-responders in six independent ICB-treated clinical cohorts (AUC: 0.65-0.78). Genomic analysis associated ANXA5 expression with distinct mutation patterns (EGFR/PTEN vs. IDH1/TP53). In vitro knockdown of ANXA5 confirmed its oncogenic role, as it suppressed glioma cell proliferation and invasion. Our study establishes ANXA5 as a prime example of a translatable biomarker discovered through multi-omics integration. It functions dually as a prognostic indicator and a predictive biomarker for immunotherapy, offering a tangible framework for patient stratification and personalized therapeutic strategies in glioma, thereby bridging a critical gap toward clinical translation.

Glioblastoma (GB) is highly malignant with a median survival of 14 months despite conventional treatments like surgery, radiotherapy, and temozolomide. Resistance to these therapies necessitates innovative approaches, such as immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1) to enhance T-cell-mediated tumor destruction. However, clinical trials have shown limited ICI efficacy in GB due to its immunosuppressive microenvironment and the blood-brain tumor barrier (BBTB), which impairs drug delivery. Emerging evidence highlights the gut microbiota as a pivotal modulator of ICI response, enhancing CD8+ and CD4+ T-cell function, antigen presentation, and immune modulation via the gut-brain axis in cancers. In addition, studies showed that gut-derived metabolites, including short-chain fatty acids, modulate immune responses and support blood-brain barrier integrity by regulating inflammatory signaling and tight junction proteins. Future GB research should prioritize clinical trials, mechanistic studies, and interventional strategies like fecal microbiota transplantation and probiotics to enhance ICI efficacy.

Electrical stimulation (ES) has emerged as a promising technique in the field of bioengineering and biomedicine, particularly in bone regeneration and cell differentiation. ES using alternating current (AC) is based on the periodic reversal of current direction, which generates oscillating electric fields. The application of an electric field has effects on cell growth and differentiation, as well as on morphology and migration. This study aimed to explore the effect of applying AC electrostimulation within the proliferation, differentiation, and morphology process of osteoblastic cells. The electrical stimulation signals were daily applied for 3 h during 14 days. Different frequencies were tested (1 Hz, 10 Hz, 100 Hz, and 1 kHz), with amplitudes of 125, 250, 500, 750, 1000, and 1500 mV/mm. Cell viability was estimated using the AlamarBlue, and MC3T3-E1 differentiation levels were evaluated through alkaline phosphatase (ALP) activity. RUNX2, OSX, ALP, OPG, and RANKL gene expression was assessed by RT-PCR. Morphological analysis was performed through cell transfection followed by immunofluorescence. Statistical analysis was conducted by SPSS.23 and graphs generated through Graph-pad. Viability and ALP activity were optimal at 10 Hz. Once the frequency was defined, RUNX2, OSX, ALP, OPG, and RANKL gene expression revealed an increase in the differentiation and osteogenic activity levels at 10 Hz and 500-750 mV/mm. As well as, morphological studies showed an increase in the area, pseudopodia length, and numbers at 500 mV 10 Hz conditions. The optimal ES condition to differentiate MC3T3-E1 cells is 10 Hz 500-750 mV/mm. Electrostimulation has emerged as a promising technique in the field of bioengineering and biomedicine, particularly in bone regeneration and cell early maturation.

Naringenin (NAR) and hesperetin (HES) are citrus flavanones that have been shown to exert various geroprotective effects. However, key regulators of these processes remain unexplored. To address this gap, we investigated the mechanisms through which NAR and HES modulate hepatic redox control, persulfidation, and senescence-associated pathways in 24-month-old male Wistar rats. Animals were treated orally with NAR or HES (15 mg/kg b.w.) for 4 weeks, while control groups remained physiologically intact or received vehicle. Liver tissue was analyzed using a dimedone-based switch method to evaluate overall protein persulfidation (P-SSH), Western blot, qPCR, and histological analysis, including quantification of IHC staining and IF labeling. Our results showed that both citrus flavanones increased total P-SSH levels while exerting distinct regulatory effects on the H2S metabolic network. Only HES upregulated gene expression of H2S-producing enzymes (cystathionine beta-synthase CBS, cystathionine gamma-lyase CSE, and mercaptopyruvate sulfurtransferase MST) and catabolic enzymes (sulfide:quinone oxidoreductase SQR and thiosulfate sulfurtransferase TST), together with CBS protein, whereas NAR decreased CSE protein expression. Both NAR and HES treatment activated the Nrf2 signaling pathway, as evidenced by increased nuclear translocation of Nrf2 in the treated groups. Concurrently, NAR and HES increased Sirt1 expression, which was accompanied by decreases in p16 and β-galactosidase expression, indicating attenuation of hepatic senescence. Together, these findings highlight a synergistic interplay among persulfidation, H2S metabolism, and Nrf2/Sirt1 signaling as a key mechanism by which citrus flavanones support hepatic resilience during aging.

Resveratrol (RSV; 3,5,4'-trihydroxy-trans-stilbene) is a natural polyphenolic compound with notable antioxidant, anti-inflammatory, and immunomodulatory properties. It has been investigated for therapeutic applications in cardiovascular disease, cancer, and neurodegenerative disorders. This review emphasizes the potential of RSV in oncology and neuroprotection, synthesizing evidence from systematic database searches and experimental studies. Despite promising biological activities, RSV is limited by poor stability, low aqueous solubility, rapid metabolism, and restricted bioavailability, necessitating improved delivery strategies such as nanoencapsulation, nanocrystals, prodrugs, and structural analogues. Mechanistically, RSV exerts anticancer and neuroprotective effects through modulation of p53, STAT3, NF-κB, and mitochondrial-mediated apoptosis. Its antioxidant actions involve regulation of reactive oxygen species (ROS), activation of NRF2, AMPK signaling, and SIRT1. RSV and related antioxidants act on multiple molecular pathways, including TP53, β-catenin, STAT3, NF-κB, NRF2-AMPK, PI3K/AKT, and SIRT1, to regulate inflammation and cell death. The balance between oxidative and antioxidative processes is critical for therapeutic efficacy. Notably, RSV-induced ROS-mediated cell death, particularly in the context of TP53 mutations, represents a promising target for future interventions. Overall, RSV demonstrates multi-target potential for cancer and neurodegenerative disease therapy, though optimization of its pharmacological profile remains essential.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. An essential early hallmark of PD is disrupted mitochondrial dynamics driven by impaired cellular energy homeostasis. Therapeutic interventions restoring mitochondrial function and biogenesis hold promise for neuroprotection in PD. In the present study, the neuroprotective effects of formononetin (FMN) were evaluated in both MPP+-induced SH-SY5Y cells and the MPTP-induced mouse model of Parkinson's disease, using concentrations of 5, 10, 20, and 40 μM in vitro and doses of 25 and 40 mg/kg in vivo. To evaluate its biological activity, we employed western blotting and immunofluorescence assay to quantify the expression of disease-relevant markers. Mitochondrial health was further assessed using Mitotracker, alongside reactive oxygen species (ROS) assessment. Motor behavior and molecular endpoint parameters were also measured. Our results demonstrated that FMN significantly attenuates MPP+/MPTP-induced neurotoxicity, improves motor function, and restores the expression of PGC-1α, tyrosine hydroxylase, and key mitochondrial proteins involved in mitochondrial DNA replication. Enhancement of mitochondrial fusion proteins and other transcriptional regulators was also observed in the administered groups. Flow cytometry and imaging analyses confirmed that FMN-mediated PGC-1α activation preserves mitochondrial integrity and reduces oxidative stress. Altogether, these findings provide evidence that formononetin exerts neuroprotective effects in PD by modulating the PGC-1α signaling axis.

Hydroxy-safflor yellow A (HSYA), a bioactive compound from Carthamus tinctorius, has reported anti-inflammatory and antitumor activities. However, its effects on breast cancer and the underlying immune mechanisms remain poorly defined. In this study, we investigated the immunomodulatory role of HSYA in breast cancer, with a focus on its impact on tumor-associated macrophages (TAMs) and T cell responses. Using in vitro assays, murine breast cancer models, and single-cell transcriptomic analysis, we found that HSYA significantly inhibited tumor growth and reshaped the tumor immune microenvironment. Flow cytometry and transcriptomic profiling revealed that HSYA treatment reduced tumor-associated macrophages (TAMs) infiltration and suppressed C-C motif chemokine ligand 5 (CCL5) expression, which was associated with enhanced recruitment and activation of tissue-resident memory T (TRM) cells. Co-culture and functional assays further supported a role for the TAM/CCL5 axis in mediating these immune effects. Collectively, our findings demonstrate that HSYA exerts antitumor activity, at least in part, by modulating the TAM/CCL5/TRM axis, highlighting its potential as an immunomodulatory therapeutic strategy in breast cancer.

Vestigial-like family member 3 (VGLL3), a transcriptional cofactor of the TEA domain family, has been previously identified as a regulator of osteoblast differentiation. Building upon our previous findings, we investigated VGLL3 function in MC3T3-E1 osteoblasts using an integrated approach combining transcriptomic analysis and functional assays to identify its downstream effectors and explore associated autophagy mechanisms. RNA-seq analysis of Vgll3-knockdown (shVgll3) cells identified death-associated protein kinase 2 (DAPK2), a regulator of autophagy, as a downstream effector. Autophagic activity was examined using transmission electron microscopy and western blot analysis of LC3-II and p62 proteins. The effects of Dapk2 knockdown (shDapk2) on osteoblast differentiation were evaluated using qPCR, western blotting, alkaline phosphatase staining, and Alizarin Red staining. Rapamycin treatment was used to determine whether pharmacologic activation of autophagy could restore osteoblast function. Vgll3 knockdown significantly suppressed autophagic flux, as evidenced by fewer autophagic vacuoles, decreased LC3-II accumulation, and increased p62 expression. A comparable reduction in autophagic activity was observed in shDapk2 cells and was accompanied by impaired osteoblast differentiation. Rapamycin treatment partially restored autophagy and osteogenic differentiation in Vgll3-deficient cells. Finally, overexpression of DAPK2 partially rescued autophagic activity and osteogenic differentiation in shVgll3 cells, supporting its role as a key downstream functional effector. FOXM1 was further implicated as a potential transcriptional regulator contributing to DAPK2 expression. Collectively, our findings suggest that VGLL3 may influence osteogenic differentiation in osteoblasts, potentially involving DAPK2-associated autophagy.

Ferroptosis is a highly synchronized form of non-apoptotic intracellular iron-dependent cell death which is regulated by multiple cellular metabolic pathways. Extensive studies suggest that ferroptosis could efficiently set the therapy resistant cancer cells on the road to ruin, thus providing new opportunities for cancer therapy. And-1 is an acidic nucleoplasmic DNA binding protein which plays a vital role in DNA replication and repair. Here in this study, we report a novel function of And-1 in regulating erastin-induced ferroptosis in ovarian cancer cells. And-1 overexpression (OE) enhanced erastin-induced ferroptosis by modulating the level of ferroptosis biomarkers such as MDA, GSH, Fe2+ and lipid peroxidation; while knockdown (KD) of And-1 produces opposite results. Moreover And-1(OE) suppressed the expression of NRF2, SLC7A11, and FTH1 and promoted the expression of TFR1 and ATF3 while And-1 (KD) produces opposite results. Further mechanistic study revealed that And-1 inhibits the expression of SLC7A11 by increasing ATF3 expression. Moreover, using pharmacological inhibitors, we have shown that erastin induces ferroptosis through multiple mechanisms. Taken together, our data suggest that And-1 enhanced erastin-induced ferroptosis in OC cells by inhibiting system xc - expression through ATF3 and suppressing NRF2 expression.

Osteoporosis is closely linked to oxidative stress and inflammation, positioning the vitamin E metabolite γ-CEHC, known for its robust antioxidant and anti-inflammatory properties, as a promising therapeutic agent. However, its molecular targets have remained largely unknown. In this study, we characterized the protein targets of γ-CEHC and clarified its role in regulating bone metabolism using an ovariectomized (OVX) mouse model and in vitro assays. Bone morphological analysis and histomorphometry demonstrated that γ-CEHC improves osteoporosis in OVX mice by inhibiting osteoclast differentiation and enhancing osteoblast differentiation. To identify the underlying mechanisms, we employed isothermal thermal proteome profiling (TPP) to map γ-CEHC-interacting proteins, followed by Gene Ontology (GO) and KEGG enrichment analyses. Our findings identified fatty acid-binding protein 5 (Fabp5) as a core target. The direct and specific binding between γ-CEHC and Fabp5 was confirmed through cellular thermal shift assays (CETSA), molecular docking-suggesting hydrogen bonding with Thr63-and Surface Plasmon Resonance (SPR) which showed a strong binding affinity (Kd = 5.24 μM). Furthermore, γ-CEHC was found to suppress LPS-induced M1 macrophage activation and promote M2 polarization, thereby reducing reactive oxygen species (ROS) levels and restoring bone remodeling homeostasis. This study is the first to systematically elucidate the molecular mechanisms of γ-CEHC in bone metabolism, revealing that it acts as a highly selective ligand for Fabp5. These findings provide a novel mechanistic basis for using γ-CEHC and targeting Fabp5 in the treatment of osteoporosis.

Inflammatory bowel disease (IBD) arises from dysregulated interactions between the immune system and the intestinal microenvironment. Finding new therapeutic targets could help to develop treatments that attenuate its severity. The present study investigated the immunomodulatory potential of bioaccessible sulforaphane (SFN, 0.100 μg/mL) from broccoli by-products. Interestingly, the main results evidenced that at this physiological concentration, SFN contributed to reducing the secretion of pro-inflammatory interleukins (IL-1β, IL-6, IL-17, IL-18, IL-23, TNF-α) by intestinal epithelium up to ~56%, whereas enhancing anti-inflammatory cytokines (IL-10, IL-4, IL-13) between ~24% and ~71%. These changes adjusted the proportion of CD86+ and CD206+ during macrophage differentiation, associated with the prevention of immune-mediated IBD. In addition, a reduction in the expression of macrophage-dependent pro-inflammatory cytokines and an augmentation of the tolerogenic classes were observed. The combined use of intestinal epithelial (Caco-2) and monocytic (THP-1) cell lines established an in vitro model of the epithelium-macrophage crosstalk, thereby enhancing the physiological relevance of our findings. These results were confirmed using a pure SFN-based model system, which demonstrated SFN's contribution to the anti-inflammatory properties of broccoli stalk and bridged the gap between in vitro findings and potential dietary/therapeutic applications. Thereby, this work demonstrated that dietary SFN contributes to a large extent to the reshaping capacity of the phytochemical burden of broccoli stalks, on the interleukin profile secreted by epithelium and macrophages, as well as the macrophage differentiation, thus supporting the valorisation of broccoli by-products for preventing and managing inflammatory conditions, such as IBD.

Pancreatic cancer (PC) remains a highly lethal malignancy with limited treatment options, largely due to its heterogeneity and therapy resistance. While ferroptosis-a form of iron-dependent cell death driven by lipid peroxidation-has emerged as a relevant pathway, its role in PC is incompletely understood, as is the oncogenic function of Centrosomal Protein 55 (CEP55). Here, we integrated TCGA data with immunohistochemical validation and demonstrated that CEP55 is significantly overexpressed in PC and correlates with advanced disease and poor prognosis. Functionally, CEP55 knockdown suppressed proliferation, migration, and clonogenicity, while inducing ferroptosis, as evidenced by elevated lipid peroxidation, iron accumulation, and glutathione depletion. Mechanistically, CEP55 silencing downregulated key ferroptosis suppressors, including GPX4, SLC7A11, and NQO1, increasing cellular sensitivity to ferroptotic stress. Erastin, a ferroptosis inducer, enhanced ferroptosis in CEP55-deficient cells and counteracted the tumor-promoting effects of CEP55 overexpression. In vivo, CEP55 silencing reduced tumor growth and altered ferroptosis markers. Our findings establish CEP55 as a novel driver of PC progression via ferroptosis suppression, supporting its potential as both a prognostic biomarker and a therapeutic target for combination strategies aimed at overcoming PC resistance.

Trifuhalol A (TFA), a phlorotannin derived from the edible brown seaweed Agarum cribrosum, has been reported to exert diverse physiological activities, yet its anti-diabetic mechanism remains unclear. This study systematically investigates the multi-targeted anti-diabetic effects of TFA, with a particular focus on enhancing glucose uptake and protecting pancreatic islets. In vitro enzyme inhibition assays demonstrated that TFA significantly inhibited the activities of α-glucosidase and α-amylase, indicating its potential to attenuate postprandial glycemic excursions by modulating carbohydrate hydrolysis. Additionally, TFA effectively suppressed the formation of advanced glycation end-products (AGEs), potentially reducing the risk of diabetes-associated complications. Mechanistically, TFA enhanced glucose uptake in C2C12 myotubes by activating the PI3K/Akt and AMPK signaling pathways, which in turn promoted the translocation of glucose transporter type 4 (GLUT4) to the plasma membrane, thereby facilitating cellular glucose utilization and insulin sensitivity. Furthermore, in vivo investigations using an alloxan-induced type 1 diabetic zebrafish further confirmed the bioefficacy of TFA, as evidenced by its capacity to reduce hyperglycemia, alleviate oxidative stress, and protect pancreatic islets, without eliciting observable systemic toxicity. Taken together, these findings provide both mechanistic and functional evidence supporting TFA as a safe and potent multi-target bioactive compound with promising applications in the development of functional foods and therapeutic strategies for diabetes management.

Dextromethorphan (DXM), a widely used antitussive agent, was investigated for its effects on mitochondrial F1FO-ATPase activity and oxidative phosphorylation. Our results demonstrate that DXM inhibited F1FO-ATPase independently of the thiol redox state. Mutual exclusion analysis highlighted an overlapping binding site between DXM and dicyclohexylcarbodiimide (DCCD), indicating a shared or adjacent binding site in the membrane-embedded FO domain of the enzyme. These findings suggested that DXM selectively targeted the proton translocation mechanism of F1FO-ATPase during the ATP hydrolysis and synthesis of ATP. Moreover, kinetic analysis confirmed a high affinity of DXM for the enzyme, with an inhibitory efficiency of 2.37 mM-1⸱s-1. Importantly, DXM did not affect electron transport chain activity but impaired ATP synthesis, as evidenced by altered respiratory control ratios of oxidative phosphorylation. The data obtained offer new insights into its off-target mitochondrial effects and potential implications for bioenergetic regulation.

This review systematically explores the dynamic regulatory roles of lysine lactylation (Kla) in the tumor microenvironment (TME) and its clinical translational potential. As an emerging post-translational modification, Kla modifies histones and non-histone proteins via lactate generated by the Warburg effect, thereby reshaping tumor metabolism and immune landscapes. Mechanistically, Kla orchestrates metabolic reprogramming and immunosuppression through key signaling pathways such as HIF-1α, mTOR, and NF-κB. Specifically, it promotes the activation of immunosuppressive cells while inhibiting cytotoxic CD8+ T cells and NK cells, fostering tumor immune escape. Preclinical studies demonstrate that targeting lactate metabolism or lactylation enzymes restores immune effector functions and enhances immune checkpoint therapy efficacy. However, challenges such as tumor heterogeneity, metabolic plasticity, and systemic toxicity remain. Future research should focus on Kla's crosstalk with other epigenetic modifications, spatiotemporal dynamics in TIME, and clinical translation to unlock its potential as a biomarker and precision oncology target.

Fermented foods are increasingly recognized for their health-promoting properties, but little is known about the effects of sauerkraut brine (SB), a by-product of cabbage fermentation, on systemic inflammation and neuro-inflammatory responses. This study aimed to investigate the immunomodulatory, antioxidant, and behavioral effects of SB oral treatment in a mouse model of low-dose lipopolysaccharide (LPS) challenge. The SB was prepared by traditional spontaneous cabbage fermentation and analyzed for pH, microbiological profile, and acidity. At the end of fermentation, the brine contained a high level of viable lactic acid bacteria (LAB) (1.8 × 106 CFU/ml). Mice were pretreated orally with SB, heat-treated SB (htSB), or saline for 4 weeks before single or repeated LPS injection (0.5 mg/kg). Safety assessments, including body weight, food intake, and locomotor activity, did not indicate adverse effects with either form of SB. In the acute LPS model, SB pretreatment significantly reduced mRNA expression of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in the prefrontal cortex compared to the saline-pretreated group. Interestingly, the expression of IL-10, strongly induced by LPS, was also significantly reduced by SB, suggesting modulation of both pro- and anti-inflammatory signaling pathways. These protective effects were less pronounced in the heat-treated SB group, suggesting that viable bacteria or heat-sensitive components may be critical for bioactivity. In the repeated LPS model, SB prevented LPS-induced depletion of glutathione (GSH) and preserved total antioxidant capacity (TAC), while heat-treated SB provided no protection and resulted in increased protein carbonylation and decreased TAC. No significant changes in the activities of antioxidant enzymes (SOD1/2, CAT, GR, GSH-Px, GST) were observed. Behavioral tests using the open-field paradigm showed that all groups exhibited prolonged sickness behavior after repeated LPS exposure, despite a two-day washout period. However, only the SB group showed delayed recovery, with reduced horizontal and vertical activity lasting 1 day longer than in the other groups. Nevertheless, pretreatment with SB and heat-treated SB prevented the LPS-induced reduction in time spent in the central zone, a commonly used measure of anxiety-like behavior, suggesting a possible anxiolytic effect. In conclusion, SB exhibits anti-inflammatory and antioxidant properties associated with systemic LPS-induced neuroinflammation and may reduce anxiety-like behavior. These effects appear to be dependent on heat-sensitive constituents or microbial viability. The findings support further investigation of SB as a functional dietary intervention targeting neuro-immune health.

Autophagy is increasingly understood as a lipid-governed membrane program rather than a solely protein-driven degradative pathway. This review combines molecular and mechanistic evidence showing how lipid molecules, metabolic enzymes, and membrane physical properties coordinate autophagy from induction to lysosomal degradation. We highlight phosphoinositide microdomains and their cognate kinases and phosphatases as spatial cues that nucleate phagophores, control maturation, and regulate lysosome reformation. We also discuss alternative phosphoinositide sources, sphingolipid and ceramide signaling, phosphatidic acid and diacylglycerol metabolism, fatty-acyl composition, and acyl-CoA signaling as determinants of membrane curvature, tension, leaflet asymmetry, and phase behavior in autophagy. Key protein effectors and their lipid binding motifs and domains are integrated into a model in which lipid chemistry and mechanics gate enzymatic activities. We present integrated lipid-protein-biophysics approaches to highlight outstanding questions and uncover predictive principles.

Sepsis induced myocardial injury (SIMI) remains a life threatening complication with mortality rates exceeding 40% to 50%, yet effective therapies are lacking. This study investigates the cardioprotective effects of eupatilin (EUP), a bioactive flavonoid derived from Artemisia argyi, and reveals a previously unrecognized mechanism involving selective modulation of KAT5 mediated histone H3K27 lactylation (H3K27la). Using an LPS induced murine model and TNF-α stimulated human AC16 cardiomyocytes, we evaluated cardiac function, inflammatory responses, and apoptotic pathways through dose response analyses. Multi omics approaches including RNA seq, metabolomics, ChIP seq, and molecular docking were integrated to dissect the pharmacodynamic profile of EUP. EUP conferred concentration dependent cardioprotection with optimal effects at 25 μM. Compared with conventional glucocorticoid therapy, EUP showed enhanced target selectivity, markedly reducing pro inflammatory cytokines such as TNF-α, IL-1β, and IL-6 while improving cardiac function parameters including ejection fraction and fractional shortening. Mechanistically, EUP bound KAT5 with high affinity, suppressed its lactylation activity, and reduced H3K27la enrichment at the promoters of inflammatory genes. Metabolic flux analysis further indicated that EUP inhibited glycolytic lactate production and restored oxidative phosphorylation. Together, these findings identify EUP as a natural modulator of the KAT5-H3K27la axis, addressing both metabolic dysregulation and epigenetic reprogramming in SIMI. With a favorable pharmacokinetic profile and superior target specificity relative to standard immunosuppressive regimens, EUP holds promise for clinical translation in sepsis associated cardiac dysfunction.

Exosomes are nanoscale extracellular vesicles (EVs) that have recently garnered significant attention owing to their crucial role in orchestrating cell-to-cell communication. Through the transfer of heterogeneous molecular cargo encompassing lipids, proteins, cytokines, growth factors, and RNAs (including mRNAs, lncRNAs, miRNAs, and circRNAs), they modulate a wide spectrum of physiological and pathological processes. Exosomes have been extensively investigated as diagnostic tools, therapeutic agents, as well as innovative platforms for drug delivery in metabolic, oncological, cardiovascular, and neurological disorders. Culminating evidence has demonstrated the pivotal role of exosomes in renal pathophysiology. Depending on their cargo content, exosomes represent potential biomarkers for early disease detection and survival prediction across various renal pathologies. While current therapeutic interventions are largely confined to attenuating disease progression, exosomes hold the potential to promote regeneration in both acute kidney injury and chronic kidney diseases. The current review comprehensively examines the clinical utility of exosomal cargo as diagnostic and prognostic biomarkers as well as therapeutic agents in kidney diseases, highlighting their crosstalk with critical signaling pathways implicated in renal pathophysiology. Addressing the current challenges in exosome isolation and standardization, and the development of advanced exosome engineering technologies are crucial for the transformation from experimental research settings to clinical practice. This should be augmented by preclinical validation and well-designed clinical trials, ultimately paving the way for a new era of precision medicine.