Biology Direct[JOURNAL]
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200 papers
Pyrroloquinoline quinone protects heat-stressed porcine oocytes and improves early embryonic development via maintaining mitochondrial integrity and redox homeostasis.
Zhang M, Xu Q, Jia B … +10 more , Zhang X, Lay K, Li M, Zou Y, Wang Z, Peng X, Gao Y, Zhou C, Xue Y, Zhang Y
Biol Direct · 2026 May · PMID 42226245 · Full text
Heat stress (HS) is a major environmental factor that impairs female fertility by disrupting oocyte quality and developmental competence. Pyrroloquinoline quinone (PQQ), a redox cofactor with strong antioxidant and mitoc...
Heat stress (HS) is a major environmental factor that impairs female fertility by disrupting oocyte quality and developmental competence. Pyrroloquinoline quinone (PQQ), a redox cofactor with strong antioxidant and mitochondrial-protective properties, has recently attracted attention for its cytoprotective roles in mammalian cells. Here, we investigated whether PQQ supplementation could alleviate HS-induced porcine oocyte damage and improve subsequent embryonic development. Our results showed that PQQ treatment significantly restored the rates of germinal vesicle breakdown (GVBD) and first polar body extrusion (PBE) in heat-stressed oocytes. PQQ markedly reduced intracellular reactive oxygen species (ROS) accumulation, enhanced mitochondrial membrane potential (ΔΨm), and maintained ATP levels, indicating improved mitochondrial function. Furthermore, PQQ attenuated DNA damage (γH2A.X foci) and apoptosis (Caspase-3 activation), preserved spindle morphology and actin distribution, and normalized cortical granule and ovastacin localization, suggesting improved cytoplasmic maturation. Importantly, embryos derived from PQQ-treated oocytes exhibited higher cleavage and blastocyst formation rates compared with the HS group. Collectively, these findings demonstrate that PQQ effectively mitigates HS-induced oocyte dysfunction by maintaining mitochondrial integrity, redox balance, and cytoskeletal organization, thereby improving oocyte competence and early embryonic development under heat stress.
Restriction-modification systems and prophages drive genomic diversification in Priestia megaterium.
Wang M, Shao C, Vílchez JI … +4 more , He D, Chen L, Zhang JL, Zhang H
Biol Direct · 2026 May · PMID 42226049 · Full text
Bacteria are frequently stressed by bacteriophages. Priestia megaterium is a bacterium of both agricultural and biotechnological importance, yet it has been unclear how the interplay between phage-imposed stress and bact...
Bacteria are frequently stressed by bacteriophages. Priestia megaterium is a bacterium of both agricultural and biotechnological importance, yet it has been unclear how the interplay between phage-imposed stress and bacterial immunity shapes the genome evolution and stability in P. megaterium. Through comparative genomics and methylome profiling, herein we show that restriction-modification (RM) systems are the dominant and ubiquitous barrier to lysogeny in P. megaterium. Intact prophages disproportionately carry anti-restriction genes, including multiple DNA methyltransferases and anti-restriction proteins, revealing the molecular strategies required to overcome the strong RM-mediated selective pressure inherent to this species. Prophage-derived genes are significantly enriched within the unique pangenome fraction and include auxiliary metabolic genes absent in host genomes. Moreover, prophage content strongly predicts phylogenetic structure in P. megaterium. Together, our findings demonstrate how defensive constraints, phage counter-adaptations, and horizontal acquisition jointly drive genomic diversification of P. megaterium.
Inhibiting the Hif-1α-Drp1 axis alleviates mitochondrial dysfunction and reduces senescence-like changes in myocardial tissue after acute myocardial infarction.
Yang P, Yang Y, Huang X … +5 more , Zhu H, Zhan Y, Cai X, Zheng Z, Tian Q
Biol Direct · 2026 May · PMID 42216043 · Full text
BACKGROUND: Cellular senescence is a significant pathological process in acute myocardial infarction (AMI), yet its upstream regulatory mechanisms remain unclear. This study reveals that the HIF-1α /Drp1 signaling axis s...
BACKGROUND: Cellular senescence is a significant pathological process in acute myocardial infarction (AMI), yet its upstream regulatory mechanisms remain unclear. This study reveals that the HIF-1α /Drp1 signaling axis serves as a critical link between hypoxia and senescence-like changes in myocardial tissue by disrupting mitochondrial homeostasis. METHODS: Using rat AMI model (in vivo) and hypoxia‑exposed H9c2 cardiomyocytes (in vitro), we assessed mitochondrial morphology, mtROS, and senescence markers. Genetic gain‑ and loss‑of‑function approaches were applied to modulate Drp1 and HIF‑1α. We further evaluated the effects of the mitochondrial fission inhibitor Mdivi‑1 and the SASP inhibitor Ruxolitinib on mitochondrial function, senescence, and apoptosis. RESULTS: AMI/hypoxia activated the ERK1/2-Akt pathway, promoting Drp1 Ser616 phosphorylation and mitochondrial translocation, leading to excessive fission, mtROS burst, and senescence-like changes in myocardial tissue (in vivo) / cardiomyocyte senescence (in H9c2 cells). HIF-1α transcriptionally regulated Drp1 expression. Mdivi-1 restored mitochondrial dynamics, reduced SASP-related inflammation, and improved cardiac function, indicating a myocardial protective effect. Ruxolitinib suppressed Drp1 Ser616 phosphorylation and alleviated senescence, apoptosis, and pyroptosis. CONCLUSION: HIF-1α-mediated upregulation of Drp1 and ERK-dependent phosphorylation of Drp1 collectively drive mitochondrial dysfunction and senescence-like changes in myocardial tissue in AMI. Targeting these pathways or the SASP pathway represents a promising therapeutic strategy.
Single-cell transcriptomic analysis deciphers heterogeneity and transcriptional regulatory programs of sepsis with different prognosis.
Yang Y, Hua Y, Yang S … +2 more , Liu N, Li J
Biol Direct · 2026 May · PMID 42215988 · Full text
Sepsis has a high mortality rate, yet the cellular heterogeneity and transcriptional regulatory programs associated with divergent clinical outcomes remain incompletely understood. Here, we integrated two peripheral bloo...
Sepsis has a high mortality rate, yet the cellular heterogeneity and transcriptional regulatory programs associated with divergent clinical outcomes remain incompletely understood. Here, we integrated two peripheral blood single-cell RNA-seq cohorts to explore prognosis-associated immune remodeling patterns in sepsis. Using reference-based annotation, pySCENIC-inferred regulon activity, pathway enrichment, and CellChat based ligand-receptor inference, we observed broad differences in cell composition, transcriptional programs, and intercellular communication between survivors and non-survivors. Non-survivors exhibited relative decrease of monocytes, B-cells, NK cells, and CD4/CD8 T cells, together with relative platelet expansion. cDC2 and plasmablasts showed relatively large transcriptional disturbance compared to other cell types. In cDC2, poor outcome was associated with increased TNF-α and NF-κB related regulon activity, which linked to AP-1 transcription factors (JUN, FOSL2, CEBPB, NFIL3, KLF6, and FOSB), together with reduced STAT1 and STAT2-associated interferon signaling. Gene regulatory network analysis highlighted cell type-specific transcription factor and target gene relationships. CellChat suggested that cDC2 may occupy a more connected position in survivors, whereas connectivity appeared reduced in non-survivors. Independent bulk transcriptomic validation supported increased FOSL2 and CEBPB expression, and a multivariable eight-transcription-factor model showed preliminary discriminatory performance. Overall, this study suggests that poor-outcome sepsis may be associated with altered cDC2 regulatory states and reduced cDC2 centered intercellular coordination.
A novel TAp63γ-Airn regulatory axis governs early myogenic gene networks.
Ciuffoli V, Piro MC, Angelin A … +6 more , Colasanto G, Zhou H, Qu J, Lena AM, Melino G, Candi E
Biol Direct · 2026 May · PMID 42210377 · Full text
Skeletal muscle development relies on tightly coordinated transcriptional programs, yet the contribution of long non-coding RNAs (lncRNAs) to myogenesis remains largely unexplored. We previously demonstrated that the tra...
Skeletal muscle development relies on tightly coordinated transcriptional programs, yet the contribution of long non-coding RNAs (lncRNAs) to myogenesis remains largely unexplored. We previously demonstrated that the transcription factor TAp63γ is upregulated during myoblast differentiation and regulates the expression of genes involved in early stages of myogenic maturation. Here, combining transcriptome profiling with p63 ChIP-seq analysis in differentiating mouse myoblasts, we identify the lncRNA Airn as a direct transcriptional target of TAp63γ. Our findings position Airn as a previously unrecognized regulator of myogenic commitment that modulates both MyoD and MyoG expression at the mRNA and protein levels. Our work uncovers a novel TAp63γ-Airn axis essential for proper skeletal muscle differentiation and with potential relevance to muscle-wasting diseases.
Extracellular serine availability regulates inflammatory skin phenotypes.
Sergio S, Montella A, Mancini M … +5 more , Lena AM, Montanaro M, Melino G, Mauriello A, Candi E
Biol Direct · 2026 May · PMID 42210307 · Full text
Serine has recently emerged as an important regulator of epidermal cell growth and skin repair, and modulation of serine metabolism through inhibition of Serine Hydroxy-Methyl Transferases (SHMTs) is already known to att...
Serine has recently emerged as an important regulator of epidermal cell growth and skin repair, and modulation of serine metabolism through inhibition of Serine Hydroxy-Methyl Transferases (SHMTs) is already known to attenuate the development of skin inflammatory features in vivo. However, the contribution of serine/glycine free diet to inflammatory skin phenotypes, including psoriasis, has not yet been explored. Here, we investigated the role of serine/glycine availability, demonstrating that serine/glycine free diet has an impact on epidermal inflammation. Using a mouse model of inflammation fed either a standard diet or a serine/glycine-deprived diet, followed by topical application of the psoriatic-like inducer IMIQUIMOD (IMQ), we observed a substantial reversal of the IMQ-induced phenotype. This effect was associated with alterations in keratinocyte proliferation and differentiation, as well as inflammatory cell infiltration, leading to reduced epidermal thickening, improved skin organization, and a decrease in CD3⁺ T-lymphocyte infiltration. Taken together, our findings expand current knowledge of the interplay between serine metabolism and the development of skin inflammatory features, providing further evidence for a link between amino acid homeostasis and disease progression. This metabolic connection may be exploited to develop alternative therapeutic strategies for the treatment and management of chronic inflammatory diseases such as psoriasis or atopic dermatitis.
Lnc00892 enhances cisplatin sensitivity by inducing apoptosis through the BTAF1/MDM2/STAT5B/XIAP axis in bladder cancer cells.
Chang Y, Sun N, Liu Y … +10 more , Jin Z, Zhang P, Wang S, Chen J, Liu J, Lin Z, Lu Y, Huang H, Huang C, Jin H
Biol Direct · 2026 May · PMID 42204712 · Full text
BACKGROUND: Chemotherapy is the primary mode of treatment for patients with advanced bladder cancer. However, because of their non-specificity, chemotherapy drugs induce many notable side effects in patients. Recent stud...
BACKGROUND: Chemotherapy is the primary mode of treatment for patients with advanced bladder cancer. However, because of their non-specificity, chemotherapy drugs induce many notable side effects in patients. Recent studies have shown that the expression of certain long non-coding RNAs (lncRNAs) is closely related to the sensitivity of tumors to chemotherapeutic drugs. Thus, lncRNAs can be exploited as markers of tumor chemotherapeutic sensitivity to improve the efficacy of chemotherapy. Here, we investigated the role of the lnc00892 in the response of bladder cancer cells to cisplatin. RESULTS: Mechanistically, both RNA pull down assay and RIP experiment showed lnc00892 bound to BTAF1, which accelerated the dissociation of TFIID from the MDM2 promoter region in cisplatin-treated bladder cancer cells. This process reduced the transcription of MDM2, promoting STAT5B protein degradation through the ubiquitination-mediated pathway. Ultimately, these events attenuated XIAP transcription and promoted bladder cancer cell apoptosis. CONCLUSION: Lnc00892 promoted bladder cancer cells apoptosis by binding to BTAF1 which further reduced MDM2/STAT5B/XIAP levels, and ultimately promoted the sensitivity of bladder cancer cells to cisplatin. Lnc00892 could be used as a marker of cisplatin chemosensitivity in the clinic to improve the outcomes of patients with bladder cancer.
Integrative single-cell and bulk analyses reveal ATF4-associated immune suppression and WNT/β-catenin signaling in osteosarcoma.
Ding X, Chen F, Zhou J … +1 more , Xu D
Biol Direct · 2026 May · PMID 42204636 · Full text
BACKGROUND: Osteosarcoma (OS) is highly heterogeneous and often exhibits an immunosuppressive tumor microenvironment, contributing to poor outcomes. The cell-type-resolved role of the ATF/CREB stress-response network, pa...
BACKGROUND: Osteosarcoma (OS) is highly heterogeneous and often exhibits an immunosuppressive tumor microenvironment, contributing to poor outcomes. The cell-type-resolved role of the ATF/CREB stress-response network, particularly ATF4, remains unclear in OS. METHODS: We integrated public OS single-cell RNA-seq and bulk transcriptome cohorts. Single-cell analyses included malignant program discovery (cNMF), regulon inference (SCENIC), and cell-cell communication (CellChat). Bulk cohorts (TARGET and GEO) were used to build and validate a prognostic model. ATF4-associated immune features were assessed using ESTIMATE, immune deconvolution, and TIDE-related metrics. WNT/β-catenin activity was evaluated by gene-set scoring. ATF4-related drugs were screened using DSigDB/Enrichr and assessed by docking. Sorafenib was selected for molecular dynamics simulation. ATF4 function was validated by siRNA knockdown (MG63, U2OS) and overexpression (HOS). RESULTS: A stress-associated malignant program showed enriched ATF/CREB activity and prominent signaling interactions. Intersecting its markers with ATF/CREB genes identified ATF3/ATF4/CREB5, which were used to construct an ATF/CREB-associated risk score (ACS) that stratified survival in TARGET and external cohorts. ATF4 showed the most consistent adverse prognostic association and remained an independent factor in multivariate analyses. ATF4-high tumors were associated with a more immunosuppressive profile and stronger WNT/β-catenin signaling, and these features tracked with the ACS. Among the compounds tested in silico, sorafenib ranked highest in docking, and subsequent molecular dynamics simulations suggested that the ATF4-sorafenib interaction can remain stable. In cell-based assays, silencing ATF4 curtailed proliferation, colony formation, and migration, accompanied by reduced β-catenin, CyclinD1, and c-MYC. By contrast, ATF4 overexpression led to the opposite pattern. CONCLUSION: Our results place ATF4 at the intersection of stress-related tumor programs, immune suppression, and WNT/β-catenin activation in OS, and this pattern is associated with poorer clinical outcomes. The ACS offers a practical way to stratify risk, and sorafenib warrants further evaluation as a potential ATF4-oriented therapeutic lead.
Dual inhibition of KDM4B and KDM5A disassembles the PAX3-FOXO1 transcriptional program in fusion-positive rhabdomyosarcoma.
Yuan J, Han Q, Ren P … +3 more , Bai F, Zhang X, Li K
Biol Direct · 2026 May · PMID 42204622 · Full text
BACKGROUND: Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by the oncogenic transcription factor PAX3-FOXO1 and is associated with poor clinical outcome. The histone demethylase KDM4B has been implicated in sustaini...
BACKGROUND: Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by the oncogenic transcription factor PAX3-FOXO1 and is associated with poor clinical outcome. The histone demethylase KDM4B has been implicated in sustaining PAX3-FOXO1-dependent transcriptional programs, but the epigenetic regulatory mechanisms supporting this network remain incompletely characterized. METHODS: We employed a deep learning-based drug discovery strategy and identified a novel small-molecule, Compound 01. Functional and mechanistic analyses were then performed to delineate cooperative interactions among KDM4B, KDM5A, and PAX3-FOXO1, and to evaluate the impact of pharmacological perturbation on the stability of this transcriptional network in FP-RMS models. RESULTS: In this study, we identified Compound 01 with dual activity against KDM4B and KDM5A that triggers proteasome-dependent loss of both proteins. Mechanistically, we uncover a reciprocal stabilization loop in which KDM4B, KDM5A, and PAX3-FOXO1 reinforce each other to sustain the PAX3-FOXO1 transcriptional state. Pharmacological disruption of this axis by Compound 01 collapses the PAX3-FOXO1-driven oncogenic transcriptional program, suppresses key downstream targets, and markedly impairs FP-RMS cell proliferation and metastatic potential. CONCLUSION: These findings identify KDM5A as a critical epigenetic partner of the PAX3-FOXO1 network and establish dual KDM4B/KDM5A targeting as a strategy to destabilize PAX3-FOXO1 transcriptional circuitry in FP-RMS.
SIRT5-dependent desuccinylation licenses UBR5-mediated degradation of TAMM41 to regulate mitochondrial metabolism in lung adenocarcinoma.
Yuan H, Hu W, Lv X … +8 more , Cao Y, Hu K, Li Y, Chen Z, Yang J, Wang Y, Zhao J, Xu C
Biol Direct · 2026 May · PMID 42186063 · Full text
Mitochondrial metabolic reprogramming is essential for lung adenocarcinoma (LUAD) progression, yet the regulatory mechanisms governing mitochondrial phospholipid synthesis remain poorly understood. TAMM41 is a mitochondr...
Mitochondrial metabolic reprogramming is essential for lung adenocarcinoma (LUAD) progression, yet the regulatory mechanisms governing mitochondrial phospholipid synthesis remain poorly understood. TAMM41 is a mitochondrial inner-membrane enzyme required for cardiolipin biosynthesis, but its role in LUAD has not been defined. Here, we show that TAMM41 is significantly upregulated in LUAD tissues and cell lines, and its high expression correlates with poor patient prognosis. Functional studies demonstrate that TAMM41 promotes LUAD cell proliferation, migration, and invasion, whereas genetic ablation of TAMM41 suppresses malignant phenotypes. Mechanistically, TAMM41 maintains mitochondrial complex I activity, ATP production, and redox homeostasis, thereby limiting oxidative stress and apoptosis. We identify the E3 ubiquitin ligase UBR5 as a specific regulator of TAMM41 stability through ubiquitination at lysine 206. Moreover, the mitochondrial desuccinylase SIRT5 directly interacts with TAMM41 and removes succinylation at lysine 45, enhancing UBR5 binding and promoting TAMM41 degradation. In vivo, TAMM41 knockout markedly inhibits LUAD xenograft growth, accompanied by impaired mitochondrial respiration and increased apoptosis. Collectively, these findings identify TAMM41 as a mitochondrial oncogenic driver in LUAD and reveal a SIRT5-TAMM41-UBR5 axis that links lysine succinylation to mitochondrial metabolic control, highlighting TAMM41 as a potential therapeutic target.
Myricetin attenuates experimental autoimmune prostatitis and inflammatory and oxidative injury in LPS-induced RWPE-1 cells potentially through modulation of MAPK/STAT3/NF-κB/Nrf2 signaling pathway.
Zhang H, Zhang D, Zhang Y … +3 more , Han Z, Teng Z, Wang Y
Biol Direct · 2026 May · PMID 42177535 · Full text
BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological condition marked by ongoing pelvic pain, inflammation, and a reduced quality of life. Increasing evidence indicates that dy...
BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological condition marked by ongoing pelvic pain, inflammation, and a reduced quality of life. Increasing evidence indicates that dysregulated immune responses and oxidative stress contribute to CP/CPPS pathogenesis. Myricetin (MYR), a natural flavonoid, has been reported to exert anti-inflammatory and antioxidant effects in multiple disease models. However, its role in CP/CPPS remains unclear. METHODS: The protective effects of MYR were evaluated in an experimental autoimmune prostatitis (EAP) mouse model and in lipopolysaccharide (LPS)-induced RWPE-1 prostate epithelial cells. Prostatic histopathology, pelvic pain behavior, inflammatory cytokine levels, immune cell infiltration, and oxidative stress markers were assessed in vivo. In vitro, inflammatory mediator expression, reactive oxygen species (ROS) production, oxidative stress status, mitochondrial function, and signaling pathway activation were examined using qRT-PCR, Western blotting, immunofluorescence, and biochemical assays. Network pharmacology analysis was used to predict potential targets and pathways associated with the effects of MYR. The involvement of Nrf2 signaling was further examined using the Nrf2 inhibitor ML385. RESULTS: MYR markedly alleviated prostatic inflammation and pelvic pain in EAP mice, accompanied by reduced serum levels of pro-inflammatory cytokines and chemokines, decreased infiltration of CD4-positive T cells and CD68-positive macrophages, and improved oxidative stress status. In LPS-induced RWPE-1 cells, MYR suppressed the expression of inflammatory mediators, reduced ROS accumulation, restored redox balance, and attenuated mitochondrial dysfunction. Mechanistically, MYR inhibited the phosphorylation of ERK, JNK, p38, and STAT3, suppressed NF-κB activation, and promoted Nrf2 signaling. Pharmacological inhibition of Nrf2 largely abolished the anti-inflammatory and antioxidant effects of MYR. CONCLUSIONS: MYR attenuated inflammation, oxidative stress, and pain-related changes in experimental prostatitis, and these effects were associated with coordinated modulation of MAPK, STAT3, NF-κB, and Nrf2 signaling pathways. These findings suggest that MYR may represent a potential candidate for further preclinical investigation in CP/CPPS.
SETD7-mediated epigenetic regulation of LncRNA XIST promotes trophoblast pyroptosis: a study in preeclampsia mouse and cell models.
Zhao X, Li L, Wang Y … +1 more , Zheng Z
Biol Direct · 2026 May · PMID 42177518 · Full text
BACKGROUND: Pre-eclampsia (PE) is a severe pregnancy-specific hypertensive disorder that poses significant risks to both maternal and fetal health. This study seeks to elucidate the mechanism by which SETD7 regulates tro...
BACKGROUND: Pre-eclampsia (PE) is a severe pregnancy-specific hypertensive disorder that poses significant risks to both maternal and fetal health. This study seeks to elucidate the mechanism by which SETD7 regulates trophoblast cell pyroptosis in PE through epigenetic mechanisms. METHODS: PE mouse model was developed, and cell model was constructed using H/R-treated HTR-8/SVneo cells. SETD7, LncRNA XIST, FOXA1, TMBIM4, GSDMD-N, cleaved Caspase-1, and NLRP3 were detected via qRT-PCR or Western blot. ELISA was employed to measure IL-1β and IL-18. ChIP was employed to assess H3K4me3 and SETD7 enrichments on the promoter of LncRNA XIST. RIP assay was applied to verify interaction of YTHDF2/m6A with FOXA1 mRNA. The stability of FOXA1 mRNA was detected. Dual-luciferase reporter and ChIP were applied to validate the interaction between FOXA1 and TMBIM4. RESULTS: SETD7 exhibited high expression in placental tissues in PE. SETD7 knockdown attenuated IL-1β, IL-18, GSDMD-N, cleaved Caspase-1, and NLRP3 levels. SETD7 suppression ameliorated PE symptoms and inhibited H/R-induced pyroptosis. Mechanistically, SETD7 may upregulate LncRNA XIST expression by increasing H3K4me3 enrichment at the LncRNA XIST promoter. LncRNA XIST recruited YTHDF2 to FOXA1 mRNA, promoted the degradation of FOXA1 mRNA and inhibited FOXA1 expression through m6A modification, thereby reducing TMBIM4 transcription and inducing trophoblast cell pyroptosis via NLRP3 inflammasome activation. CONCLUSION: In the sFlt-1-induced PE mouse model and H/R-treated HTR-8/SVneo cells, SETD7 promotes placental trophoblast cell pyroptosis and exacerbates PE-like symptoms through the LncRNA XIST/FOXA1/TMBIM4 axis.
Naringin and hesperidin protect ovarian granulosa cells from cisplatin-induced mitochondrial dysfunction by enhancing bioenergetics and mitophagy.
Liu J, Elmorsy EM, Abdeen A … +14 more , Anajirih N, Elgendy FS, Abdelkareem HM, Nasr HE, Elwia SK, Sherif MA, El-Shaer NO, El-Wakeel HS, Shukry M, Ibrahim SF, Ali S, Gebba MA, Abu-Almakarem AS, Ge Q
Biol Direct · 2026 May · PMID 42174625 · Full text
BACKGROUND: Cisplatin (CDDP) is a widely deployed chemotherapeutic medication used to treat various solid tumors, but its clinical utility is limited by dose-dependent ovarian toxicity. Naringin (NG) and hesperidin (HD)...
BACKGROUND: Cisplatin (CDDP) is a widely deployed chemotherapeutic medication used to treat various solid tumors, but its clinical utility is limited by dose-dependent ovarian toxicity. Naringin (NG) and hesperidin (HD) are two naturally occurring flavonoids found in citrus fruits and have protective effects on mitochondrial function. RESULTS: The current study examined the protective effects of NG and HD on CDDP-induced mitochondrial dysfunction and cytotoxicity in granulosa cells. The cells are treated with CDDP alone or with NG or HD. CDDP reduced cell viability, ATP synthesis, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP), and mitochondrial complex functions in a dose-dependent pattern. It also altered mitochondrial dynamics and enhanced glycolytic activity, as exhibited by lactate levels. MMF increased, and fatty acid composition changed, resulting in a higher unsaturated/saturated ratio. PINK1 and PARKIN levels were reduced upon CDDP treatment, suggesting mitophagy disruption. Co-treatment of NG and HD enhanced complex activity, MMP, OCR, ATP generation, and cell viability. MMF was protected by NG and HD, which also stabilized fatty acids and enhanced ion permeability and mitochondrial swelling. Compared to NG, HD preserved numerous attributes more effectively and restored them almost completely. CONCLUSIONS: NG and HD effectively preserve mitochondrial bioenergetics, structure, and dynamics in granulosa cells, mitigating CDDP-induced dysfunction. These findings highlight their potential as natural adjuvants to reduce ovarian toxicity and support fertility preservation in female cancer patients.
Transcutaneous auricular vagus nerve stimulation alleviates chronic heart failure by targeting cathepsin K/p53-mediated ferroptosis.
Zhao L, Lu Y, Hu Y … +7 more , Dai S, Wang X, Zhai X, Pu L, Hua B, Wang J, Zhao L
Biol Direct · 2026 May · PMID 42169167 · Full text
BACKGROUND: Heart failure remains a major global health challenge, with ferroptosis implicated in its pathogenesis. Transcutaneous auricular vagus nerve stimulation (taVNS) has shown therapeutic potential for heart failu...
BACKGROUND: Heart failure remains a major global health challenge, with ferroptosis implicated in its pathogenesis. Transcutaneous auricular vagus nerve stimulation (taVNS) has shown therapeutic potential for heart failure, but its regulatory mechanism underlying myocardial ferroptosis remains unclear. METHODS: Isoproterenol-induced chronic heart failure (CHF) rats received taVNS for 2 weeks. Cardiac function was assessed by echocardiography, while myocardial pathology was analyzed using histological staining. Ferroptosis was evaluated via flow cytometry, transmission electron microscopy, and detection of ferroptosis markers. In vitro, Ang II-stimulated H9C2 cells were treated with Ach or subjected to cathepsin K knockdown. RESULTS: The taVNS treatment improved LVEF and reduced LVIDd/LVIDs in CHF rats, accompanied by attenuated hypertrophy and fibrosis as well as decreased NT-proBNP, TNF-α, and IL-6 levels. Additionally, taVNS suppressed ferroptosis in cardiac tissues of CHF rats, as evidenced by reduced ROS and Fe²⁺ levels, decreased iron deposition, and upregulated SLC7A11 and GPX4 expression. However, the mAChR and α7-nAChR antagonists (atropine and MLA) abolished these benefits of taVNS. Moreover, taVNS inhibited cathepsin K/p53 pathway to suppress ferroptosis in CHF rat cardiac tissues, rescuing SLC7A11 and GPX4 expression and reducing ROS and Fe²⁺ levels. Acetylcholine replicated taVNS effects in vitro, reversing Erastin-induced ferroptosis and suppressing cathepsin K/p53 pathway. CONCLUSION: The taVNS treatment modulated cholinergic receptor activation to suppress cathepsin K/p53-mediated ferroptosis, ameliorating cardiac dysfunction in CHF. These findings revealed the specific mechanism by which taVNS exerted cardioprotection via cholinergic receptors, offering a novel therapeutic strategy for CHF.
Single-cell analysis reveals that NRG1/3-ERBB4 signaling affects metabolic reprogramming and immune escape in Wilms tumor.
Gao Z, Lin J, Tang H … +10 more , Li A, Li R, Xu A, Hu R, Xu S, Zhang M, Yang W, Huang H, Zhang Z, Liu F
Biol Direct · 2026 May · PMID 42163376 · Full text
BACKGROUND: Wilms tumor presents a heterogeneous tumor microenvironment. This study aimed to characterize the tumor microenvironment and identify prognostic genes to improve therapeutic strategies. METHODS: We integrated...
BACKGROUND: Wilms tumor presents a heterogeneous tumor microenvironment. This study aimed to characterize the tumor microenvironment and identify prognostic genes to improve therapeutic strategies. METHODS: We integrated single-cell RNA sequencing and transcriptomic data from paired tumor and normal tissues. Bioinformatics analyses included assessments of cellular heterogeneity, trajectories, and cell-cell communication. Prognostic genes were identified with differential expression, Cox regression, and machine-learning analyses. Furthermore, functional characterization, immune infiltration patterns, and therapeutic targets were systematically investigated. Potential therapeutic compounds were predicted using drug databases and a graph-based deep learning framework to predict compound-protein interactions. RESULTS: Single-cell RNA sequencing revealed 17 cell clusters, with tumor-specific epithelial cells and renal progenitor cells. Pseudotime trajectory analysis revealed dynamic differentiation, highlighting NRG1/3-ERBB4 signaling. Intersection of the transcriptomic and single-cell data identified 405 key genes. A prognostic model incorporating eight prognostic genes (PRLR, SLC16A7, SGIP1, PPARGC1A, CDHR5, GRB7, FKBP10, and UGT2B7) stratified patients into high- and low-risk groups (p < 0.0001), with area under the curve values > 0.6 for 1-, 2-, and 3-year survival prediction. High-risk patients had elevated regulatory T cell infiltration and immune checkpoint genes (TNFRSF9 and KIR3DL3). Chitosan was identified as a multitarget agent that interacts with the eight prognostic proteins. CONCLUSIONS: This study defined tumor cellular architecture and identified eight prognostic genes with potential clinical value.
The Wnt/StarD7 axis protects retinal ganglion cells from glutamate excitotoxicity by inhibiting ferroptosis.
Zhang L, Chu W, Feng X … +4 more , Peng H, Guo L, Yang Y, Kong L
Biol Direct · 2026 May · PMID 42157244 · Full text
BACKGROUND: Glutamate (Glu) accumulation-induced excitotoxicity is a major cause of retinal ganglion cell (RGC) death in glaucoma, and the role of ferroptosis, a novel form of cell death, is critical in this process. The...
BACKGROUND: Glutamate (Glu) accumulation-induced excitotoxicity is a major cause of retinal ganglion cell (RGC) death in glaucoma, and the role of ferroptosis, a novel form of cell death, is critical in this process. The aim of this study was to investigate the function and regulatory mechanisms of the lipid transport protein StarD7 in RGC ferroptosis. METHODS: An N-methyl-D-aspartate (NMDA)-induced retinal excitotoxicity mouse model and a Glu-induced RGC cell model were constructed for experimental investigation. RT‒qPCR and Western blotting were used to assess the expression of related genes and proteins, HE staining was used to assess pathological retinal damage, and kits were used to evaluate ferroptosis-related indicators. RESULTS: Ferroptosis was involved in NMDA-induced RGC damage in glaucoma mice. StarD7 expression was upregulated in glaucoma, and overexpression of StarD7 decreased the levels of total iron, Fe, ROS, and MDA in vitro and in vivo while increasing the expression levels of GSH, GPX4, and xCT, thereby suppressing RGC ferroptosis. Mechanistically, Glu treatment significantly reduced the expression of the Wnt signaling pathway proteins Wnt1 and β-catenin. Activating the Wnt/β-catenin pathway promoted StarD7 expression, which in turn inhibited Glu-induced ferroptosis in mRGCs. CONCLUSION: The Wnt/β-catenin signaling pathway inhibits Glu-induced RGC ferroptosis by upregulating StarD7 expression, revealing the potential neuroprotective role of StarD7 in glaucoma treatment and providing a scientific basis for the development of new therapeutic strategies. CLINICAL TRIAL NUMBER: Not applicable.
Decoding the Snail transcriptional network: its role in cancer progression and therapy.
Parfenyev SE, Nazarov AN, Daks AA … +3 more , Fedorova OA, Barlev NA, Shuvalov OY
Biol Direct · 2026 May · PMID 42152116 · Full text
The transcription factor Snail is a central regulatory hub that governs the transition from localized tumorigenesis to invasive, metastatic, therapy-resistant disease. Elucidating the mechanisms of Snail-driven epithelia...
The transcription factor Snail is a central regulatory hub that governs the transition from localized tumorigenesis to invasive, metastatic, therapy-resistant disease. Elucidating the mechanisms of Snail-driven epithelial-mesenchymal transition (EMT) and identifying strategies to target this pathway are critical challenges and promising frontiers for novel oncology therapeutics. In this review, we systematically analyzed the association between Snail expression and patient outcomes across multiple malignancies based on bioinformatics and statistical interrogation of clinical datasets and molecular interaction networks. Our findings indicate that Snail primarily exerts its oncogenic effects by directly activating a network of pro-metastatic and pro-survival oncogenes, rather than by repressing epithelial genes. We further show that the canonical E-box motif (CANNTG) is a poor predictor of Snail targets. Instead, Snail's tumor-promoting activity is largely mediated through its cooperation with EGR1/SP1 transcription factors on non-canonical TCACA promoter elements, which upregulate genes such as ZEB1, MMP9, and LEF1. Based on these conclusions, we propose a refined model for predicting Snail target genes. Finally, given that inhibiting the Snail-EMT axis presents a plausible opportunity to limit cancer progression and improve patient outcomes, we also discuss clinically relevant pharmacological strategies for targeting Snail.
NPC2 deficiency as a potential target drives malignancy and chemo-resistance in DLBCL.
Yuan Y, Wu Q, Li X … +1 more , Xu P
Biol Direct · 2026 May · PMID 42143364 · Full text
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) remains challenging to treat, with a considerable proportion of patients exhibiting chemo-resistance and poor prognosis. A deeper understanding of the molecular mechanism...
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) remains challenging to treat, with a considerable proportion of patients exhibiting chemo-resistance and poor prognosis. A deeper understanding of the molecular mechanisms underlying lymphoma progression and therapy failure is urgently needed. METHODS: Using bioinformatic analysis of single-cell RNA-seq datasets, we identified NPC2 as a potential target associated with poor outcomes. Its function was explored in SU-DHL-4 and SU-DHL-2 cells by shRNA-mediated knockdown, followed by in vitro and in vivo experiments including qPCR, functional assays, flow cytometry, and xenograft models in NOD‑SCID mice. RESULTS: Low NPC2 expression was correlated with worse prognosis in DLBCL patients. NPC2 depletion did not affect cell proliferation, cell cycle, or apoptosis, but induced mitochondrial dysfunction, ROS accumulation, and enhanced migration and invasion. Importantly, NPC2 knockdown conferred resistance to vincristine both in vitro and in vivo, and promoted distant tissue damage in mouse models. CONCLUSIONS: Our study identifies NPC2 as a key regulator of DLBCL aggressiveness and chemo-resistance by modulating mitochondrial function and cell motility. NPC2 may serve as a novel potential therapeutic target for improving DLBCL treatment.
Elevated NDUFAF2 expression correlates with poor prognosis and drives metabolic dependency in hepatocellular carcinoma.
Zeng P, Wang J, Lu W … +2 more , Li Z, Huang A
Biol Direct · 2026 May · PMID 42143347 · Full text
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic options for advanced and immunotherapy-resistant cases. Mitochondrial oxidative phosphorylation (OXPH...
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic options for advanced and immunotherapy-resistant cases. Mitochondrial oxidative phosphorylation (OXPHOS) has emerged as a key metabolic dependency in a subset of HCCs, yet the molecular regulators of this vulnerability remain poorly understood. Here, we report that NDUFAF2, a core assembly chaperone for mitochondrial Complex I, is significantly overexpressed across multiple human cancers, particularly in HCC, where elevated expression correlates with poor overall survival, progression-free interval, and disease-specific survival in large-scale TCGA and CPTAC cohorts. At the transcriptomic and proteomic levels, NDUFAF2 upregulation was consistently observed in primary HCC tissues compared with paired normal liver samples, and correlated with advanced histological grade, pathological stage, high AFP levels, and vascular invasion. Bioinformatic pathway analyses identified OXPHOS as the dominant biological process associated with NDUFAF2 expression. Mechanistically, stable NDUFAF2 knockdown in two independent HCC cell lines (HCC-LM3 and SNU-449) resulted in profound mitochondrial dysfunction, including reduced oxygen consumption rate, impaired ATP production, increased reactive oxygen species (ROS) accumulation, and compensatory upregulation of glycolytic genes. These metabolic defects ultimately led to suppressed cell proliferation in vitro. Preliminary correlative analyses further suggested weak associations between NDUFAF2 expression and immunosuppressive features in the tumor microenvironment, although these trends remain hypothesis-generating and require experimental validation. Collectively, our findings establish NDUFAF2 as a pivotal regulator of mitochondrial bioenergetics and malignant progression in HCC, identifying it as a promising prognostic biomarker and a potential target for metabolic therapy in OXPHOS-dependent liver cancers.
Dysregulated competitive splicing between circular and linear RNAs characterizes hepatocellular carcinoma tumorigenesis and recurrence.
Jiang S, Cui N, Nie L … +3 more , Shen J, Zhu X, Li H
Biol Direct · 2026 May · PMID 42135846 · Full text
Hepatocellular carcinoma (HCC) remains a global health challenge with a high recurrence rate, highlighting the need to decipher its underlying molecular mechanisms. While circular RNAs (circRNAs) are known to regulate ge...
Hepatocellular carcinoma (HCC) remains a global health challenge with a high recurrence rate, highlighting the need to decipher its underlying molecular mechanisms. While circular RNAs (circRNAs) are known to regulate gene expression, the landscape of competitive splicing-the dynamic balance between back-splicing and linear splicing-during HCC initiation and recurrence remains largely unexplored. Leveraging rRNA-zero RNA-seq data from GSE169289 (comprising 34 primary, recurrent, and non-recurrent HCC samples with paired controls), this study utilized an upgraded SUVA pipeline to systematically profile circRNA-associated alternative splicing events. By integrating four distinct algorithms, we identified 9,652 high-confidence circRNAs. Our analysis revealed extensive differential splicing events distinguishing tumor from normal tissues, and notably, recurrent from non-recurrent tumors, with host genes enriched in chromatin remodeling and ubiquitin-dependent pathways. Specifically, we observed a conserved attenuation in the competitive splicing of the LARP1B circRNA in tumor tissues, which correlated with host gene downregulation and poor prognosis. In the context of recurrence, circ-KLHL8 exhibited specific splicing suppression; in silico modeling suggests a potential mechanism where circ-KLHL8 loss relieves the sponging of miRNAs, thereby suppressing the tumor suppressor GLYCTK. Furthermore, RBP-circRNA co-regulatory network analysis implicated HNRNPU and CPSF4 as potential upstream regulators of initiation-related splicing, and DKC1 as a modulator of recurrence-associated events. Collectively, this study provides the first systematic characterization of the competitive splicing landscape in HCC, proposing a novel theoretical framework and candidate targets for diagnostic and therapeutic interrogation.
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