Background The occurrence of muscle atrophy in chronic kidney disease (CKD) is a prevalent complication with serious consequences but lacks effective treatment. Modulating the gut microbiota offers a promising new therapeutic approach. Shenshuai Yingyang Jiaonang (SSYYJN) is a clinically validated prescription of traditional Chinese medicine for muscle atrophy in CKD, yet the molecular basis for its therapeutic action requires elucidation. Purpose To evaluate the therapeutic efficacy of SSYYJN against CKD-induced muscle atrophy, investigate the mechanism from the perspective of the gut microbiota, and explore potential strategies for enhancing the treatment efficacy of SSYYJN. Methods A rat model of CKD with concomitant muscle atrophy was established by 5/6 nephrectomy. 16S rDNA sequencing and fecal microbiota transplantation (FMT) experiments were conducted to elucidate the gut microbiota’s role in SSYYJN efficacy. Untargeted metabolomics profiling and the pharmacological network analysis were conducted to investigate the potential mechanism of Faecalibacterium prausnitzii (FP) probiotics on SSYYJN. The regulatory mechanism of SSYYJN in CKD-associated muscle atrophy was validated through in vitro C2C12 cell experiments. Results In patients with CKD-associated protein-energy wasting (PEW), effective SSYYJN treatment improved mid-arm muscle circumference, hand grip strength, mid-arm circumference, and serum albumin. Moreover, post-hoc microbiome analysis revealed that the abundance of FP was higher in treatment-responsive patients. In a CKD rat model, SSYYJN conferred protection against renal injury, malnutrition, and muscle atrophy, this therapeutic effect was related to the gut microbiota modulation. Of note, a higher abundance of FP was also observed in SSYYJN-treated CKD rats. Further analyses suggested that FP was associated with increased levels of carnosol and may enhance EGFR/PI3K/AKT signaling, thereby potentiating the therapeutic effect of SSYYJN against CKD-induced muscle atrophy. Conclusion These findings suggest a gut microbiota-dependent mechanism underlying the action of SSYYJN against muscle atrophy in CKD. FP may be linked to the effects of SSYYJN, potentially involving the generation of carnosol and the upregulation of the EGFR/PI3K/AKT pathway, representing a targeted therapeutic strategy.

Hyperhomocysteinemia (HHcy), characterized by plasma homocysteine concentrations exceeding 15 μmol/L, has been associated with various issues that impact personal health and offspring well-being. This study examines the effect of maternal HHcy induced by a high-methionine diet on the fertility of female offspring mice. The results showed that maternal HHcy caused the overactivation of primordial follicles in female offspring mice by promoting the phosphorylation of key factors, including RPS6, mTOR, FOXO3a, and AKT. Moreover, the number of mitochondria in mature oocytes decreases, and mitochondrial function decreases, further leading to increased reactive oxygen species (ROS) levels, a higher degree of DNA damage, and spindle abnormalities, ultimately impairing the quality of oocytes. These findings demonstrate that maternal HHcy decreases offspring fertility by inducing primordial follicle overactivation and impairing oocyte quality, providing new insights into the pathological mechanisms through which HHcy affects the reproductive potential of offspring.

Background Endometriosis (EMs) is often classified as a benign disease; however, it exhibits malignant biological characteristics. Collapsin Response Mediator Protein 4 (CRMP4) has been implicated in the regulation of cell migration and invasion via its effects on the cytoskeleton, but its role in EMs remains unclear. This study investigates the role of CRMP4 in the pathogenesis of endometriosis, particularly in ectopic endometrial stromal cells (EcESCs). Methods We utilized a human endometrial ectopic stromal cell line (ihESCs), primary eutopic(Eu-ESCs), ectopic(Ec-ESCs) and control(CON-EuESCs) endometrial stromal cells, plus clinical samples. CRMP4 expression was disrupted with siRNA or lentiviral vectors; phenotypic changes were assessed by Transwell and wound-healing assays. A free-actin detection kit quantified polymerization and depolymerization. Stable ihESC cell lines overexpressing or knockout CRMP4 were analyzed by immunofluorescence, Western blot, and qPCR for MRTF/SRF axis activity after actin-modulating drugs. An in vivo mouse model received CRMP4-silencing lentivirus to evaluate lesion size and number; MRTF/SRF levels were examined by IHC, IF, WB and qRT-PCR. Results CRMP4 expression was significantly elevated in EcESCs and correlated positively with ASRM staging. CRMP4 promoted the polymerization of free actin, enhancing motility and invasiveness of endometrial stromal cells. It facilitated the nuclear translocation of MRTF, activating SRF and increasing the expression of downstream target genes related to migration and invasion. Targeting CRMP4 inhibited the growth of endometriosis lesions. Conclusion CRMP4 critically promotes actin polymerization and the invasive behaviors of ectopic mesenchymal cells in endometriosis by activating the MRTF/SRF axis. Targeting CRMP4 offers a promising therapeutic and diagnostic strategy for endometriosis.

This study examined the effect of prior tuberculosis infection on clinical outcomes in patients with good ovarian reserve. Based on the POSEIDON criteria, we analyzed data from 5,381 women with normal ovarian reserve who underwent fresh in vitro fertilization (IVF) cycles. Through stratified analysis, we compared the clinical characteristics, IVF laboratory parameters, and clinical outcomes between TB-naïve and TB-cured patients within POSEIDON Group 1 and Group 2. TB-cured women had significantly lower pregnancy rates (OR 0.766, 95

Female genital tuberculosis (FGTB) is a major cause of infertility in regions where it is common, causing permanent damage to the reproductive tract. It mainly causes fibrosis and blockage of the fallopian tubes, directly hindering gamete movement. Meanwhile, FGTB leads to a decline in ovarian reserve and function by disrupting folliculogenesis in the ovaries, resulting in decreased levels of anti-Müllerian hormone (AMH). Mycobacterium tuberculosis also affects endometrial receptivity by inhibiting the STAT3/VEGF pathway and the imbalance of Th1/Th2 immune responses. This review explains these mechanisms and offers a multi-omics approach for early detection, identifying taurine deficiency in endometrial fluid and the TLR8 rs3764880 polymorphism as potential predictive markers. Importantly, we point out that first-line anti-tuberculosis therapy (ATT) may worsen ovarian damage by causing mitochondrial dysfunction in oocytes. For treatment, we propose the TB-FertiScore to assist personalized management: patients with a high risk (score ≥7) and severe tubo-ovarian damage should receive ATT combined with IVF, while those with less severe disease might benefit from ovulation induction along with intrauterine VEGF treatment. This comprehensive approach allows for precise, risk-based fertility preservation in areas heavily affected by the disease.

BackgroundThe presence of diminished ovarian reserve (DOR) poses a significant threat to female fertility, with no current effective treatment available. Inflammation plays pivotal roles in the pathogenesis of DOR. α-Cyperone (AC) exhibits notable anti-inflammatory and anti-oxidative properties; however, its potential for improving DOR remains unexplored.MethodsThe PubChem, PharmMapper, and SwissTargetForecast databases were queried to retrieve biochemical information and drug targets for AC. The identification of disease targets for DOR involved referring to the OMIM and Genecards databases. AC’s therapeutic targets against DOR were determined by examining the overlap between drug targets and disease targets. To analyze GO function enrichment, KEGG pathway, and disease association, the Metascape database was utilized. The results were then visualized using Cytoscape software. Receptor-ligand interaction between AC and target sites was validated through molecular docking investigations utilizing Pymol and AutoDock program software. The effect of AC on granule cell function was verified in CTX-induced DOR granule cell model. The actual AC-binding proteins in the cells were identified by Lip-MS, and the effects of AC on target protein genes were verified by RT-qPCR.ResultsFollowing the integration of 466 drug targets with 1,529 disease targets, we identified 257 AC targets for the treatment of DOR. We recorded the top 20 enriched biological processes, molecular functions, and KEGG pathways that potentially contribute to the anti-DOR effect of AC. Employing the MCC algorithm, we identified key TOP22 proteins. The docking studies revealed that AC binds strongly to all 22 proteins studied. The CTX-induced DOR granule cell model was successfully established, which was verified by detecting the levels of AMH, ROS, MMP and cell viability, indicating that AC enhanced the function of DOR granule cells. The abnormal expression patterns of MAP2K1, AKT1, ESR2, ERBB2, CDH1, CYP19A1, ESR1 and MAPK8 genes were also reversed. In addition, the binding of AC to MAP2K1, GSK3B and MAPK14 was verified by Lip-MS experiments.ConclusionAC can improve CTX-induced KGN proliferation and improved the function of KGN cell. The mechanism may be due to the targeted binding ability of AC to domains of MAP2K1, MAPK14 and GSK3B. AC’s potential therapeutic targets are comprehensively explored in this study, as well as theoretical support for its use in the treatment of DOR is provided.

The deterioration of metaphase II (MII) oocyte quality is a principal factor compromising fertility in women of advanced maternal age and a core hallmark of ovarian aging; however, effective interventions to counteract this age-related decline are currently lacking. Although salidroside (Sal) exhibits health-promoting and anti-aging properties, its protective effects against MII oocyte aging and the underlying mechanisms remain poorly understood. In this study, we demonstrated that salidroside supplementation significantly improved multiple aspects of MII oocyte quality, particularly oocyte maturation and developmental competence. Comprehensive transcriptomic analysis revealed that salidroside rescues aged oocyte quality primarily by enhancing oxidative phosphorylation (OXPHOS). This enhancement effectively reduced reactive oxygen species (ROS) accumulation, thereby attenuating DNA damage and apoptosis. Furthermore, we identified that differentially expressed genes in the OXPHOS pathway were predominantly enriched in the subunits of mitochondrial respiratory chain complex I. The protective effects of salidroside in aged MII oocytes were markedly abolished by rotenone, indicating that salidroside primarily exerts its beneficial effects through mitochondrial complex I-mediated OXPHOS. Together, our findings highlight salidroside supplementation as a promising therapeutic strategy to ameliorate age-related MII oocyte deterioration, delay ovarian aging and improve reproductive outcomes. Future studies should focus on the translational potential of this intervention for human clinical applications.

B-cell acute lymphoblastic leukemia (B-ALL) is a prevalent hematological malignancy, posing difficulties in identifying efficacious treatment strategies for refractory and recurrent patients. Our research revealed that coactivator-associated arginine methyltransferase 1 (CARM1) was highly expressed in B-ALL and associated with unfavorable prognostic outcomes. Down-regulation and inhibition of CARM1 effectively suppressed proliferation and colony formation of B-ALL, while also inducing apoptosis and cell cycle arrest. Mechanistically, inhibition or down-regulation of CARM1 reduced PARP1 level and contributed to double-strand breaks (DSBs) accumulation. Inhibition of CARM1 and PARP1 synergistically supressed B-ALL development. Significantly, the inhibition of CARM1 was found to promote memory differentiation and reduce the exhaustion of CD19-CAR-T cells. Taken together, CARM1 inhibition not only suppressed B-ALL but also enhanced the durability of CAR-T cells against B-ALL, which provides novel insights into the tumor suppression and immune regulation of CARM1 inhibition on cancer therapy.

The molecular mechanisms governing mRNA accumulation during oocyte growth, essential for developmental competence, remain poorly understood. This study investigates the role of Matrin-3 (MATR3), a highly expressed RNA-binding protein in growing oocytes (GOs), using oocyte-specific knockout mouse models and human oocyte maturation arrest (OMA) samples. The results showed that MATR3 was more abundant in GOs than fully-grown oocytes (FGOs), highly expressed in the nucleus of non-surrounded nucleolus (NSN) oocytes, and exited the nucleus during the NSN-to-surrounded nucleolus (SN) transition. In OMA patients, MATR3 nuclear localization was missed, with smaller oocytes than FGOs. Further, Matr3 deletion in mouse GOs caused restricted oocyte growth, global transcription disorders, follicle development failure, blocked GO-granulosa cell communication (via reduced Gdf9 and Radixin expression), and infertility. Mechanistically, MATR3 regulated transcription by recruiting H3K9me2-demethylating lysine-specific demethylase 3B or binding target gene promoters, like Radixin . These findings reveal a critical role of MATR3 in orchestrating transcription and paracrine signaling during oogenesis and suggest its potential as a diagnostic and therapeutic target for OMA.

Background Recent studies indicate that approximately 15% of couples worldwide are affected by infertility. The discovery of female germline stem cells (FGSCs) offers a promising new therapeutic strategy for infertility treatment.The objective of this study is to elucidate the regulatory role of epibrassinolide in the development of FGSCs and its underlying mechanism. Methods We developed an in vitro FGSC culture system treated with 24-epibrassinolide (EBR, E1641, Sigma), a bioactive brassinosteroid. Proliferation was quantified via CCK-8 assays and EdU incorporation; apoptotic levels of cells following drug treatment were assessed by flow cytometry and TUNEL assay; differentiation status was assessed by western blotting, immunofluorescence, and qRT-PCR. For exploring mechanisms，we performed long-read RNA-seq, RNA in situ conformation sequencing (RIC-seq), tagged RNA affinity purification, LC-MS/MS proteomics, single-molecule RNA FISH, and RNA immunoprecipitation. Results EBR significantly enhanced FGSC development by coordinately regulating: (1) meiotic progression acceleration and (2) apoptotic pathway suppression. Integrative RIC-seq/longRNA-seq analysis revealed EBR reinforces spatial interactions between lncRNA Gm26624 and transporter gene Abcg2. Mechanistically, N-myristoyltransferase 1 (NMT1) functions as an RNA-binding scaffold facilitating this RNA-RNA interaction. Functional validation established the EBR-induced Gm26624-Abcg2 axis as both necessary and sufficient for meiotic entry initiation. Conclusions We identify a phytohormonal signaling pathway orchestrating FGSC fate determination through an NMT1-mediated RNA interactome. These findings elucidate fundamental germline stem cell regulation principles and provide proof-of-concept for plant-derived compounds as promising reproductive therapeutics.

Three-dimensional (3D) chromatin architecture undergoes dynamic reorganization during mammalian gametogenesis and early embryogenesis. While mouse studies have shown species-specific patterns as well as mechanisms underlying de novo organization, these remain poorly characterized in humans. Although RNA polymerases II and III have been shown to regulate chromatin structure, the potential role of RNA polymerase I (Pol I), which drives ribosomal RNA production, in shaping 3D genome organization during these developmental transitions has not been investigated. We employed a modified low-input in situ Hi-C approach to systematically compare 3D genome architecture dynamics from gametogenesis through early embryogenesis in human and mouse. Complementary Smart-seq2 for low-input transcriptomics, CUT Tag for Pol I profiling, and Pol I functional inhibition assays were performed to elucidate the mechanisms governing chromatin organization. Our study revealed an extensive reorganization of the 3D genome from human oogenesis to early embryogenesis, displaying significant differences with the mouse, including dramatically attenuated topologically associating domains (TADs) at germinal vesicle (GV) stage oocytes. The 3D genome reconstruction timing is a fundamental difference between species. In human, reconstruction initiates at the 4-cell stage embryo in human, while in mouse, it commences at the 2-cell stage embryo. We discovered that Pol I is crucial for establishing the chromatin structures during mouse embryogenesis, but not in human embryos. Intriguingly, the absence of Pol I transcription weakens TAD structure in mouse female germline stem cells, whereas it fortifies it in human counterparts. These observed interspecies distinctions in chromatin organization dynamics provide novel insights into the evolutionary divergence of chromatin architecture regulation during early mammalian development. Our findings provide mechanistic insights into species-specific chromatin organization during germ cell and embryonic development and have potential implications for fertility preservation and birth defect prevention.

The insufficient activation, infiltration, and functional suppression of tumor-killing cells in the tumor microenvironment (TME) collectively hinder antitumor immunity. CCR7, CXCL16, and GITRL are well-established immune modulators with potential to enhance immunotherapy efficacy. Herein, we developed lipid nanoparticle-encapsulated mRNA (LNP-mRNA) encoding these three targets with the aim of enhancing dendritic cell (DC) immunogenicity and improving the immunosuppressive TME. DCs were stimulated in vitro with LNP-mRNA to evaluate its effects on DC function. The systemic immune response of LNP-mRNA was characterized. To assess the antitumor effect of LNP-mRNA, B16-OVA tumor-bearing mouse models were constructed. Humanized Raji-engrafted mouse models were constructed to investigate the synergistic effect of LNP-mRNA and anti-PD-1 antibody. Results demonstrated that LNP-mRNA enhanced the function of DCs. Furthermore, LNP-mRNA promoted T cell activation and effector differentiation while suppressing regulatory T cell infiltration. Intratumoral administration of LNP-mRNA elicited potent immune response and induced regression of established tumors. In humanized Raji-engrafted mouse models, the combination use of LNP-mRNA and anti-PD-1 antibody synergistically amplified antitumor immunity. Overall, our research demonstrates that the synthesized LNP-mRNA enables durable tumor control through coordinated enhancement of DC functionality, T cell priming, and immunosuppressive TME remodeling. This multi-functional strategy marks a transformative advancement in tumor immunotherapy.

Rationale: Colorectal cancer (CRC) is a leading cause of cancer-related mortality. Epigenetic modifications play a significant role in the progression of CRC. KAT7, a histone acetyltransferase, has an unclear role in CRC. Methods: In this research, we analyzed the expression of KAT7 in CRC patients and its correlation with prognosis using the GEO database, western blot, and immunohistochemistry. We assessed the impact of KAT7 on CRC cell functions through cell viability, colony formation, flow cytometry, scratch, and transwell assays. Mechanistic insights were obtained via RNA sequencing and ChIP-qPCR. Additionally, we evaluated the effects of KAT7 on CRC growth and metastasis in vivo using mouse subcutaneous tumor and lung metastasis models. Results: In this study, we discovered an upregulated KAT7 signaling pathway in CRC and its association with poor patient survival. Knockdown of KAT7 promotes apoptosis and inhibits proliferation, migration, and invasion of CRC cells. Conversely, KAT7 overexpression enhanced these cellular processes. In vivo assays confirmed that knockdown of KAT7 can inhibit CRC proliferation and lung metastasis. Mechanistically, KAT7 acetylated histone H3 at lysine 14 (H3K14) to enhance MRAS transcription, which activated the MAPK/ERK pathway and promoted tumorigenesis. The enzymatic function of KAT7 as an acetyltransferase is crucial for the advancement of colorectal cancer. In KAT7 knockdown CRC cells, re-expression of KAT7, but not an acetyltransferase-deficient mutant, rescued MRAS expression, ERK phosphorylation, and CRC tumorigenesis. Conclusion: We found that KAT7 is highly expressed in CRC patients, and those with high KAT7 expression have a worse prognosis. KAT7 enhances MRAS gene transcription by promoting H3K14 acetylation, thereby activating the MAPK/ERK pathway and promoting malignant phenotypes of CRC. In summary, KAT7 represents a promising target for CRC therapy.

Chimeric antigen receptor (CAR) therapies have demonstrated remarkable clinical efficacy in hematological malignancies, validating their therapeutic potential. However, challenges such as therapeutic resistance and limited accessibility hinder their broader application. To overcome these limitations, alternative CAR-based cell therapies, including CAR-Natural Killer (CAR-NK), CAR-macrophage (CAR-M), and CAR-dendritic cell (CAR-DC) therapies, have been proposed. Compared with CAR-T, CAR-NK cells have a higher safety profile in terms of cytokine release syndrome (CRS) and neurotoxicity, while being naturally cytotoxic, making them a promising option. Despite these advantages, CAR-NK therapy is limited by issues such as insufficient tissue infiltration and low transduction efficiency. CAR-M cells, with their potent infiltration capabilities and ability to function as antigen-presenting cells, also hold promise but face challenges related to suboptimal viral transduction efficiency. CAR-DCs are emerging as a highly promising approach and are currently undergoing active investigation. This review summarizes the profiles, current clinical trials, and comparative advantages and limitations of CAR-T, CAR-NK, CAR-M, and CAR-DC therapies. Finally, we discuss the key challenges to be addressed and the future prospects of these evolving CAR-based cell therapies.

Objective: Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine levels, is associated with adverse pregnancy outcomes, though its mechanistic link to placental dysfunction remains unclear. This study aimed to explore how HHcy disrupts placental development to identify conserved molecular mechanisms related to adverse pregnancy outcomes. Methods: We develop murine HHcy model using a high-methionine diet and observe placental and fetal developmental outcome at key pregnancy times (E7.5, E10.5, E13.5). Structural and functional anomalies were detected histopathologically and molecularly to examine potential placental pathology. Expression profiles in placental tissues were determined by transcriptome profiling to describe dysregulated pathways. Expression and activity of lysosomal-autophagy were examined by qRT-PCR, western blotting, and transmission electron microscopy. Clinical validation was performed using placental samples from spontaneous abortion (SA) patients with HHcy and without HHcy and matched controls. Results: HHcy-exposed mice exhibited significant reductions in embryo implantation rates and fetal viability, accompanied by impaired placental growth and structural disorganization. Histological analysis revealed atrophy of the ectoplacental cone, dilation of intervillous spaces, and diminished labyrinthine/junctional zones. Transcriptomic data highlighted enrichment of lysosomal and inflammatory pathways, corroborated by molecular evidence of lysosomal overload, suppressed autophagy-related gene expression and dysregulated autophagic flux. Placental samples from SA patients with HHcy mirrored these molecular alterations. Conclusion: Our findings suggest that HHcy disrupts placental homeostasis, impairs lysosomal function, and triggers maladaptive autophagy, leading to adverse pregnancy outcomes. The conserved pathways suggest targeting the lysosomal-autophagic axis might treat HHcy-related pregnancy problems.

Hyperandrogenism is one of the key leading causes of polycystic ovary syndrome (PCOS), which is a complex metabolic disorder affecting 6% to 20% of women of reproductive age. However, the molecular pathogenetic mechanisms responsible for androgen excess in PCOS remain largely unknow. While most previous studies have specifically focused on ovarian tissue, few have evaluated the role of extraovarian organs in PCOS. Here, it is found that KLF9 expression is up-regulated in murine primary hepatocytes treated with DHEA. Notably, the genetic ablation of Klf9 in hepatocytes significantly alleviated the progression of DHEA induced PCOS in mouse. Conversely, hepatic Klf9 transgenic mice displayed a spontaneous PCOS-like phenotype. Mechanistically, hepatic KLF9 is directly activated by intranuclear AR and then directly binds to the promoter of Srd5a1 and the gene loci of Hsd3b3, which encode the enzyme for the conversion of DHEA to dihydrotestosterone, to promote its transcription in the liver. Overall, our study indicated that the liver plays a vital role in the development of PCOS and that hepatic KLF9 might be a potential therapeutic target for PCOS.

Diminished ovarian reserve (DOR) is a multifactorial gynecological disorder that has emerged as a significant global health challenge. Currently, there are no effective preventive or therapeutic strategies for DOR. Exosome-derived long non-coding RNAs (lncRNA) in follicular fluid (FF) plays a crucial role in follicular development. We identified exosome-derived lncRNA LIPE-AS1 from the FF of DOR patients, which regulates histone deacetylase 3 (HDAC3) expression by competitively binding to miR-330-5p. Exosomes, as nanosized membrane vesicles, can deliver therapeutic agents in a targeted manner through ligand modification. In this study, we employed engineered exosomes combined with lncRNA for ovary-targeted therapy of DOR. First, we elucidated the role of lncRNA LIPE-AS1 in the pathogenesis of DOR. Next, we generated exosomes with high LIPE-AS1 expression (Exo-LIPE-AS1) using 293 T cells. Co-culture of Exo-LIPE-AS1 with oocytes from DOR models enhanced oocyte maturation and improve oocyte quality in vitro. Finally, we developed FSHβ-modified, LIPE-AS1-loaded exosomes (ExoFSHβ-LIPE-AS1), which demonstrated enhanced ovarian delivery efficiency in vivo. Consequently, ExoFSHβ-LIPE-AS1improved fertility outcomes in DOR models. Our findings demonstrate that exosomes serve as effective targeted vehicles for lncRNA LIPE-AS1, offering potential preventive and therapeutic benefits for DOR.

In recent years, increasing evidence has shown that metals play important roles in both innate and adaptive immunity. An emerging concept of metalloimmunotherapy has been proposed, which may accelerate the development of immunotherapy for cancers. Here, we discuss how metals affect T cell function through different signaling pathways. Metals impact the fate of T cells, including their activation, proliferation, cytotoxicity, and differentiation. Most importantly, metals also participate in mitochondrial operation by regulating energy production and reactive oxygen species homeostasis in T cells. We also identified the metal-based mutual effects between tumor cells and T cells in the tumor microenvironment. Overall, the antitumor effect of T cells can be improved by targeting metal metabolism and metalloimmunotherapy, which will be a step forward in the treatment of cancers.

Skeletal muscle atrophy is a prevalent complication in chronic kidney disease (CKD), and its pathogenesis is closely related to inflammation and oxidative stress. P-Coumaric acid (PCA) is a phenolic acid with anti-inflammatory and antioxidant pharmacological actions. This research aims to investigate the effect of PCA on CKD-induced muscle atrophy and its underlying mechanism. In our study, in vivo and in vitro models were established by using 5/6 nephrectomized rats and LPS-induced C2C12 myoblasts. The experimental results showed that PCA ameliorated kidney injury in CKD rats and increased skeletal muscle weight and the cross-sectional area of muscle fibres. In both CKD rats and LPS-induced C2C12 myoblasts, PCA also exhibited anti-inflammatory and antioxidant effects, reduced the levels of pro-inflammatory cytokines and enhanced the activity of antioxidant enzymes. Network pharmacology studies have identified 165 common targets between PCA and skeletal muscle atrophy. Furthermore, the experimental results also demonstrated that PCA decreased the expression of TLR4, MyD88, NF-κB p65, MurF1 and MAFbx at both the protein and mRNA levels. Additionally, in vitro experiments showed that the use of TLR4 agonists could reverse the muscle-protective effect of PCA. In summary, this study illustrated that PCA ameliorated skeletal muscle atrophy in CKD rats by inhibiting the TLR4/MyD88/NF-κB pathway.

Multiple myeloma (MM) is a hematological malignancy that remains incurable, primarily due to the high likelihood of relapse or development of resistance to current treatments. To explore and discover new medications capable of overcoming drug resistance in MM, we conducted cell viability inhibition screens of 1504 FDA-approved drugs. Lomitapide, a cholesterol-lowering agent, was found to exhibit effective inhibition on bortezomib-resistant MM cells in vitro and in vivo. Our data also indicated that lomitapide decreases the permeability of the mitochondrial outer membrane and induces mitochondrial dysfunction in MM cells. Next, lomitapide treatment upregulated DRP1 and PINK1 expression levels, coupled with the mitochondrial translocation of Parkin, leading to MM cell mitophagy. Excessive mitophagy caused mitochondrial damage and dysfunction induced by lomitapide. Meanwhile, PARP14 was identified as a direct target of lomitapide by SPR-HPLC-MS, and we showed that DRP1-induced mitophagy was crucial in the anti-MM activity mediated by PARP14. Furthermore, PARP14 is overexpressed in MM patients, implying that it is a novel therapeutic target in MM. Collectively, our results demonstrate that DRP1-mediated mitophagy induced by PARP14 may be the cause for mitochondrial dysfunction and damage in response to lomitapide treatment.