Mitochondrial dysfunction is a hallmark of diverse metabolic and neurodegenerative disorders, often linked to impaired coenzyme Q10 (CoQ10) homeostasis. Here, we have evaluated the activity of hydroxyhydroquinone (HHQ) as a novel modulator of mitochondrial metabolism. Molecular simulations revealed that HHQ can act as an alternative aromatic substrate for human COQ2 in the CoQ10 biosynthetic pathway. In cultured cells, HHQ exposure (5.10[- 5] mol.L[- 1]) enhanced complex I activity while maintaining stable ATP levels. HHQ reduced nitric oxide accumulation without altering superoxide dismutase activity, suggesting selective redox modulation. By bypassing the 4-hydroxybenzoic acid (PHBA) pathway, HHQ restores mitochondrial homeostasis and supports aerobic metabolism. These findings highlight HHQ as a small aromatic compound with strong redox potential that may favor metabolic functions driven by CoQ10 deficiency and mitochondrial dysfunction.

N6-methyladenosine (m6A) methylation modification plays an essential role in cancer development. This study focused on the mechanism exploration of m6A methyltransferase 3 (METTL3) and its downstream target gene nuclear protein-1 (NUPR1) in hepatocellular carcinoma (HCC). Detection of mRNA and protein was completed using real-time quantitative polymerase chain reaction and Western blot. Cellular behaviors were evaluated by CCK-8, EdU, flow cytometry and transwell assay. Ferroptosis was analyzed via Fe2+ level and oxidative indicators. Methylated RNA immunoprecipitation (MeRIP) was performed for validating m6A modification. RIP and dual-luciferase reporter assay were used to confirm METTL3 and NUPR1 combination. Animal research was implemented for METTL3 and NUPR1 analysis in vivo. METTL3 was overexpressed in HCC. METTL3 silencing suppressed HCC cell proliferation and invasion, while enhancing apoptosis and partially inducing ferroptosis. METTL3 downregulation reduced NUPR1 level. METTL3 induced m6A modification of NUPR1 in an IGF2BP2-dependent manner. Tumor-inhibitory effects of METTL3 knockdown were counteracted by NUPR1 overexpression. METTL3 promoted HCC tumor growth and suppressed ferroptosis in vivo by regulating NUPR1. These findings suggested that METTL3 facilitated cell invasion and partially inhibited ferroptosis through catalyzing m6A methylation modification of NUPR1, validating the specific regulatory axis METTL3/NUPR1 in HCC progression.

Angiogenesis plays a significant role in the progression of idiopathic pulmonary fibrosis (IPF). The RNA-binding protein IGF2BP3 is associated with fibrosis and angiogenesis, but its role in IPF angiogenesis remain unclear. Additionally, Tianlongjie (TL) has been confirmed to inhibit IPF progression, but the role of IGF2BP3 in this process also needs to be elucidated. A bleomycin (BLM)-induced pulmonary fibrosis rat model was established via intratracheal instillation of BLM, and an angiogenesis cell model was constructed by treating HPMVECs with VEGF165. HE staining was used to detect lung tissue injury. Masson staining, HYP content measurement, Western blot, and Immunohistochemistry assessed to evaluate fibrosis and angiogenesis progression. EdU staining was employed to detect cell proliferation. RIP-qPCR and dual-luciferase reporter assays were performed to examine the interaction between IGF2BP3 and HIF-1α. IGF2BP3 was abnormally highly expressed in pulmonary fibrosis. IGF2BP3 knockdown reduced the expression of HYP, COL-I, COL-III, α-SMA, CD31, CD34, and VEGFA in pulmonary fibrosis rat lung tissues, increased E-cadherin expression, and inhibited pulmonary fibrosis progression and microvascular formation in rats. In vitro, IGF2BP3 knockdown suppressed cell proliferation, migration and vascular endothelial cell angiogenesis. Mechanistically, IGF2BP3 may promote HIF-1α stability through m6A modification, and HIF-1α overexpression attenuated the inhibitory effect of IGF2BP3 knockdown on angiogenesis. Furthermore, TL treatment was associated with reduced fibrosis and lower IGF2BP3/HIF-1α expression. In conclusion, IGF2BP3 can promote pulmonary fibrosis-related angiogenesis by stabilizing HIF-1α expression, and TL inhibits IGF2BP3 and HIF-1α expression, angiogenesis and fibrosis progression in pulmonary fibrosis rats.

Rapid eye movement sleep deprivation (REM-SD) is associated with increased oxidative stress, characterized by disruption of the oxidant-antioxidant balance and accumulation of reactive oxygen species (ROS). Melatonin may act as a potential modulator of REM-SD-associated oxidative alterations through its circadian regulatory effects, direct ROS scavenging activity, and support of endogenous antioxidant defense mechanisms. This study aimed to evaluate the effects of melatonin treatment administered during the six-day REM-SD period or during the recovery period following REM-SD on oxidative stress-related parameters in 8-12-week-old male Sprague-Dawley rats (n = 84). REM-SD was induced using the modified multiple platform method (MMPM). Biochemical markers reflecting oxidative balance, including total antioxidant status (TAS), total oxidant status (TOS), the lipid peroxidation product malondialdehyde (MDA), non-enzymatic antioxidant glutathione (GSH), and enzymatic antioxidants, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels, were assessed using the enzyme-linked immunosorbent assay (ELISA). The findings demonstrated that REM-SD predominantly affected enzymatic antioxidant defense-related parameters. Melatonin modulated these responses, mainly by increasing enzymatic antioxidant levels and reducing lipid peroxidation. However, no significant change was observed in TOS, whereas the effect on TAS was limited and time-dependent. During the recovery period, several oxidative stress markers partially normalized, indicating a possible reactivation of endogenous antioxidant defenses. In conclusion, six-day MMPM-induced REM-SD appears to alter oxidative stress-related parameters, while melatonin may help attenuate some of these alterations by modulating antioxidant defense mechanisms. These effects varied according to the timing of administration and the specific parameter examined.

The regulatory mechanism of the long noncoding RNA SNHG6 in acute pulmonary embolism (APE) remains unclear. This study aimed to investigate the potential molecular mechanisms of SNHG6 in APE. This study established a clinical cohort comprising 120 APE patients and 120 healthy controls. It combined in vitro experiments using human pulmonary arterial smooth muscle cells (PASMCs) with in vivo experiments employing an autologous blood clot model of APE in Sprague-Dawley (SD) rats, measuring mean pulmonary artery pressure (mPAP). RT-qPCR was used to detect target gene expression. The CCK-8 assay evaluated cell proliferation, while the ELISA and western blot assays measured the relevant protein levels. The RIP assay and dual luciferase assay validated the target binding relationship. SNHG6 was significantly overexpressed in both serum samples from APE patients and lung tissues from model rats. In this exploratory case-control cohort, serum SNHG6 exhibited significant discriminatory capacity between APE patients and healthy controls (AUC = 0.9145) and showed an independent cross‑sectional association with APE status in multivariate analysis within this selected cohort. However, because serum SNHG6 was measured after diagnosis, this association should be interpreted strictly as a correlative finding rather than as evidence of prospective predictive or etiologic value. These findings require validation in clinically relevant populations with differential diagnoses. Mechanistic studies revealed that SNHG6 targeted and regulated miR-429, which in turn targeted DUSP1. In cultured PASMCs, SNHG6 acted as a competitive endogenous RNA to sequester miR-429, thereby releasing its suppression on the downstream target gene DUSP1. This upregulated the expression of proliferation-related molecules such as NOR-1 and PCNA, positively regulating PDGF-BB-induced PASMC cell proliferation. Animal experiments performed at a 7‑day subacute endpoint demonstrated that SNHG6 perturbation was associated with altered mean pulmonary artery pressure and early proliferative molecular markers during the early phase following embolic challenge. In cultured PASMCs, specific sponging of miR-429 by SNHG6 may attenuate the inhibitory effect of miR-429 on DUSP1, potentially contributing to exacerbated APE pathological manifestations.

Epidemiological studies indicate that modern lifestyle choices are closely linked to the global rise in chronic inflammatory diseases. While considerable research has explored the role of the microbiome in inflammation, a definitive causal relationship has yet to be established. Intestinal epithelial cells (IECs) play a critical role in maintaining a protective barrier that prevents the translocation of harmful molecules and pathogens. Any disruption or compromise to the integrity of these cells can impair this barrier function, facilitating the entry of potentially harmful substances and microorganisms, which subsequently triggers acute inflammatory responses. Microbial dysbiosis is one of the most prominent outcomes of inflammation in the gut, and various therapeutic strategies are currently under investigation to address this imbalance. Among these, probiotics have demonstrated potential in modulating immune and inflammatory responses by altering the composition of the gut microbiota. However, findings from preclinical and clinical studies suggest that probiotics may interfere with the re-establishment of native microbial communities and, in some vulnerable individuals, may even aggravate inflammation. In contrast, postbiotics bioactive compounds produced during the fermentation process by probiotics are emerging as a promising and safer alternative. Increasing scientific evidence supports their beneficial biological effects. In this review, we aim to discuss the most recent findings regarding the anti-inflammatory and immunomodulatory properties of postbiotics, with particular emphasis on key parental probiotic strains.

NIMA-related kinase 2 (NEK2) is a serine/threonine kinase that plays crucial roles in cellular events such as centrosome separation, cell cycle progression, spindle assembly checkpoint (SAC) regulation, and microtubule stabilization. However, its regulatory function during oocyte meiotic maturation remains unclear. In this study, NEK2 activity was inhibited using the specific inhibitor MBM-55 to evaluate its role in oocyte meiotic maturation and early embryonic development. NEK2 depletion impaired multiple indicators associated with oocyte maturation and decreased the maturation rate. Mechanistic analysis suggested that NEK2 inhibition altered spindle organization and chromosome alignment, which may be associated with impaired kinetochore-microtubule (K-MT) interactions and altered SAC-associated signaling, collectively contributing to MI-stage arrest and increased aneuploidy. In addition, NEK2 deficiency impaired the actin network, reducing spindle migration, preventing the efficient repair of accumulated DNA damage and ultimately leading to apoptosis. NEK2 inhibition in oocytes reduced subsequent embryonic developmental competence, leading to a lower blastocyst formation rate. These findings demonstrate that NEK2 is a critical regulator of porcine oocyte meiotic maturation through its roles in SAC regulation, K-MT attachment, cytoskeletal dynamics, and the DNA damage response.

Colorectal cancer (CRC) is still a deadly malignancy all over the world. Previous studies have indicated that exosomes could remodel the microenvironment and promote tumor development. Furthermore, Galectin 3 (also known as LGALS3) was found to be present within the lumen of exosomes and participate in tumor progression. However, the effects of exosomal LGALS3 on CRC progression are still unclear. The advanced CRC cellular heterogeneity was identified in GSM7349819 database using scRNA-Seq analysis. Through the analysis of GSM7349819 database, transcriptome GSE159112 database, and GeneCards database, potential targets of lipid metabolism-related differential expression genes (DEGs) in macrophages and stem cells during CRC progression were identified. LGALS3 and Y-box binding protein 1 (YBX1) expression was determined using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. M2 polarization of macrophages was determined by measuring the M2-specific cell surface markers and cytokines. Binding between LGALS3 and YBX1 was analyzed using m5C RIP, RIP, and dual-luciferase reporter assays. PMA-treated THP1 cells were exposed to IL-4 and IL-13, generating M2-TAMs (THP1-M2). Effects of M2-TAM-derived exosomal YBX1 and LGALS3 on CRC development were assessed. Cell proliferation, invasion, sphere formation ability, and apoptosis were determined using EdU, Transwell, sphere formation, and flow cytometry. Oil Red O staining was applied for lipid accumulation. Role of M2-TAM-derived exosomal YBX1 on CRC tumor growth was determined in vivo experiments. Public database analysis exhibited that lipid metabolism-related gene LGALS3 was upregulated in CRC stem cells and M2 macrophages. Compared with THP1-M0, LGALS3 was increased in THP1-M2. LGALS3 was transferred from M2 TAMs to CRC cells via exosomes. M2 TAM-derived exosomal LGALS3 knockdown repressed CRC cell proliferation, invasion, stemness, lipid metabolism, promoted apoptosis, and inhibited tumor growth in vivo. Mechanistically, YBX1 recognized m5C modifications in LGALS3 mRNA and maintained mRNA stability in M2 TAM. YBX1-mediated m5C modification of exosomal LGALS3 derived from M2 TAM could promote CRC cell growth and lipid metabolism, providing a highly potential target for CRC.

Endothelial dysfunction is a hallmark of hypertension and a key contributor of hypertensive vascular damage. Mitochondrial oxidative stress serves as a central mediator that triggers endothelial dysfunction in hypertension. Activating Transcription Factor 4 (ATF4) is a key regulator of cellular stress responses; however, its role in maintaining endothelial mitochondrial redox homeostasis under hypertension remains to be fully elucidated. Through integrated bioinformatic profiling of public mouse aortic single-cell RNA sequencing (scRNA-seq) datasets, we identified a cell-type-specific upregulation of ATF4 within the endothelial cell cluster under both Angiotensin II (Ang II) and high-salt treatment, which was further validated in hypertensive murine aortas and Ang II-stimulated human umbilical vein endothelial cells (HUVECs). To investigate its functional role in vivo, endothelial-specific ATF4 overexpression was achieved via adeno-associated virus (AAV) delivery in Ang II-infused mice, which blunted blood pressure elevation and attenuated vascular damage. To dissect the underlying mechanisms in vitro, loss- and gain-of-function assays were performed in HUVECs using siRNA knockdown and adenovirus-mediated overexpression. Mechanistically, chromatin immunoprecipitation (ChIP-qPCR) and luciferase reporter assays demonstrated that ATF4 directly bound to the isocitrate dehydrogenase 2 (IDH2) promoter and transcriptionally activated its expression. Crucially, IDH2 knockdown recapitulated the detrimental effects of ATF4 silencing, confirming it as an important downstream mediator. Collectively, these findings demonstrate that the endothelial ATF4-IDH2 axis constitutes a novel protective pathway that safeguards mitochondrial redox homeostasis in hypertensive vascular damage. These findings suggest that ATF4-mediated transcriptional reprogramming of mitochondrial antioxidant defense may represent a promising therapeutic strategy for hypertensive vascular damage.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes. The glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide exerts renoprotective effects beyond glucose control; however, the underlying mechanisms remain incompletely understood. The protective effects and mechanisms of liraglutide were investigated using in vitro (HK-2 cells under glucolipotoxic conditions) and in vivo (DKD rat) models. Key molecular and functional assessments included the evaluation of oxidative stress, apoptosis, mitochondrial function (dynamics (MFN1, MFN2, FIS1, and DRP1), mitophagy (PINK1, PARKIN, LC3II/I, and P62), and ultrastructure), and histone acetylation (H3K9/14/18/27ac). The critical role of the NQO1/SIRT3 pathway was validated using pharmacological inhibition and genetic silencing (shRNA/AAV). Both in vitro and in vivo, a multifaceted injury phenotype, including oxidative stress, apoptosis, mitochondrial dysfunction, and histone hyperacetylation, was induced, accompanied by downregulation of the NQO1/SIRT3 pathway. Disruption of this pathway further exacerbated these injuries. Conversely, liraglutide treatment effectively counteracted this phenotype, improving metabolic parameters (blood glucose, blood insulin, and blood lipids), renal function (blood urea nitrogen, serum creatinine, and urine albumin-to-creatinine ratio) and histopathology. Liraglutide attenuated oxidative stress and apoptosis, restored mitochondrial function and mitophagy, and reduced histone hyperacetylation. These protective effects were consistently associated with the restoration of NQO1/SIRT3 expression. Genetic or pharmacological disruption of the NQO1/SIRT3 axis significantly attenuated the efficacy of liraglutide, and combined inhibition completely abolished its effects. Our findings demonstrate that liraglutide attenuates DKD by activating the NQO1/SIRT3 pathway, which coordinates the enhancement of mitochondrial function and the restoration of epigenetic homeostasis. This study revealed that the NQO1/SIRT3 pathway is a critical mechanistic mediator of the renoprotective effect of liraglutide.

Glaucoma is a leading cause of irreversible blindness, characterized by progressive loss of retinal ganglion cells (RGCs), with glutamate excitotoxicity being a key contributor to RGC damage. Eugenol, a natural phenolic compound, has been shown to exhibit neuroprotective properties. However, protective effect of eugenol on glaucoma has not been explored. This study aimed to evaluate neuroprotective effects of eugenol in models of glutamate excitotoxicity and to explore the underlying mechanisms. The glutamate-induced R28 cell excitotoxicity model and N-methyl-D-aspartate (NMDA)-induced mouse glaucoma model were established. Cell Counting Kit-8 (CCK-8), iron ion probes, lipid peroxidation detection and other techniques were employed to elucidate whether eugenol could alleviate glutamate-induced ferroptosis. Subsequently, in vivo validation was performed using C57BL/6J mice. Eugenol significantly attenuated glutamate-induced R28 cell death and RGC damage. Eugenol restored Mitofusin 2 (Mfn2) levels reduced by glutamate excitotoxicity, thereby reducing abnormal lipid droplet (LD) accumulation and alleviating mitochondrial dysfunction. Furthermore, it upregulated solute carrier family 7 member 11 (SLC7A11), increased cellular glutathione (GSH) levels, and activated glutathione peroxidase 4 (GPX4) in an Mfn2-dependent manner, ultimately inhibiting ferroptosis. Eugenol exerts neuroprotective effects in glaucoma excitotoxicity models by suppressing ferroptosis through Mfn2-mediated regulation of mitochondrial-LD homeostasis and the SLC7A11/GSH/GPX4 antioxidant pathway.

Infertility has long been a major health concern worldwide, with male infertility accounting for approximately half of all cases. In recent years, increasing evidence has shown that long non-coding RNAs (lncRNAs) are involved in the regulation of spermatogenesis. LncRNA AK015322 is a testis-specific lncRNA that is highly expressed in testicular tissue. Previous studies have demonstrated that lncRNA AK015322 promotes the proliferation of spermatogonial stem cells (C18-4) in vitro; however, its role in spermatogenesis in vivo remains unclear. To investigate the effects of lncRNA AK015322 gene knockout on spermatogenesis in male mice. LncRNA AK015322 knockout mice (C57BL/6J) were generated using CRISPR/Cas9 technology. Computer-aided sperm analysis was performed to evaluate sperm parameters in knockout mice. In addition, transcriptome sequencing was conducted to identify potential regulatory genes and signaling pathways associated with lncRNA AK015322. Compared with wild-type mice, lncRNA AK015322-deficient mice exhibited delayed epididymal development, increased sperm morphological abnormalities, and significantly reduced sperm motility. Transcriptome sequencing of testicular tissues identified 98 significantly upregulated genes and 109 significantly downregulated genes in knockout mice. Gene ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses indicated that lncRNA AK015322 may be involved in pathways such as the Hippo signaling pathway and androgen response. Differentially expressed genes were further validated by RT-qPCR. LncRNA AK015322 plays an important role in spermatogenesis, and its deletion leads to impaired sperm function and delayed epididymal development in mice.

Chronic heart failure (CHF) is a severe end-stage syndrome of multiple cardiovascular diseases, associated with unfavorable clinical prognosis. This study aimed to investigate the expression profile, clinical value and molecular mechanism of BCYRN1 in regulating myocardial cell injury in CHF. Quantitative real-time PCR (qRT-PCR) was applied to detect the expression level of BCYRN1. The Receiver operating characteristic (ROC) curves was used to evaluate its diagnostic performance, and Kaplan-Meier survival analysis was performed to explore the correlation between BCYRN1 and patient prognosis. Hydrogen peroxide (H2O2) was used to establish a cardiomyocyte injury model. CCK-8 assay, flow cytometry, ELISA, and Western blot were used to detect cell viability, the apoptosis rate, inflammatory cytokines secretion, and the proteins related to apoptosis, respectively. Dual-luciferase reporter assay was conducted to verify the molecular binding relationships. BCYRN1 and BAX were significantly upregulated, whereas miR-455-3p was downregulated in CHF patients. BCYRN1 exhibited reliable diagnostic efficacy for CHF; High BCYRN1 expression was correlated with lower 36-month survival. BCYRN1 knockdown improved cell viability, suppressed apoptosis and reduced inflammatory cytokine release in H2O2-treated cardiomyocytes. Mechanistic validation revealed that BCYRN1 acts as a competitive endogenous RNA (ceRNA) to sponge miR-455-3p, thereby releasing its inhibitory effect on BAX. Rescue experiments confirmed that inhibiting miR-455-3p abrogated the protective effect of BCYRN1 silencing on cardiomyocytes. Inhibiting BAX expression reversed the detrimental effects of the miR-455-3p inhibitor on cardiomyocytes. BCYRN1 may represent a potential biomarker for CHF diagnosis and prognosis. It worsens H2O2-driven inflammatory injury and apoptosis in cardiomyocytes via the miR-455-3p/BAX axis, which may represent a potential novel molecular target in CHF treatment.

Non-small cell lung cancer (NSCLC) with KRAS[G12C] mutation is associated with poor prognosis and resistance to standard therapies. Sotorasib, a KRAS[G12C] tyrosine kinase inhibitor, has shown clinical efficacy, yet its interaction with different irradiation modalities remains unclear. This study aimed to evaluate the potential radiosensitizing effect of Sotorasib in such mutated cells exposed to X-rays or carbon-ion (C-ions) irradiation. Two human NSCLC cell lines (H358, KRAS[G12C]; and A549, KRAS[G12S]) were treated with Sotorasib alone or in combination with X-rays or C-ions irradiation (1-8 Gy). Cell viability, clonogenic survival, and sphere-forming ability and cytokines were assessed. Sotorasib alone specifically reduced the clonogenic capacity of H358 cells to ~ 30% while no effect was observed with A549 cells. Interestingly, Sotorasib combined with X-ray irradiation decreased clonogenic survival compared with either treatment alone, without evidence of synergy. In contrast, a synergistic effect was observed with C-ions in H358 cells (β = -0.36, 95% CI [- 0.52 to - 0.20], p < 0.001; enhancement ratio = 4.21 at SF2). C-ions irradiation alone markedly reduced sphere formation in both cell lines, whereas sotorasib showed no additional impact. GM-CSF expression was downregulated with sotorasib alone while IP-10 was upregulated when H358 cells were irradiated with sotorasib, suggesting an immune-specific modulatory response. A specific radiosensitization of KRAS[G12C] -mutated NSCLC cells was observed when associating Sotorasib with C-ions. This represents the first evidence of synergistic enhanced cytotoxicity from combining KRAS[G12C] inhibition with high-LET radiation. These findings support further in vivo and translational studies exploring C-ions therapy as a promising strategy for KRAS[G12C]-mutated NSCLC.

Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of targeted treatment. Previous studies have shown that the deubiquitinase UCHL1 is significantly upregulated in TNBC tissues and positively correlated with shorter overall survival in patients, suggesting that UCHL1 may drive TNBC progression. The latest research suggests that ferroptosis deficiency can promote tumor metastasis, but it is still unclear whether UCHL1 affects TNBC by regulating ferroptosis. Based on the potential role of UCHL1 in ferroptosis, we propose the hypothesis that UCHL1 enhances the survival and invasion ability of TNBC cells by inhibiting ferroptosis. We downloaded the single-cell RNA sequencing dataset for breast cancer (GSE176078) from the Gene Expression Omnibus database and integrated it with The Cancer Genome Atlas data to conduct bioinformatics analysis, focusing on identifying key genes related to TNBC. We performed gene set enrichment analysis (GSEA) to explore the pathways associated with UCHL1. After that, we validated the expression of UCHL1 in TNBC tissues and cell lines and examined its influence on cell proliferation, migration, and invasion through functional experiments. Finally, we explored the downstream targets of UCHL1, utilizing co-immunoprecipitation, western blot, immunofluorescence colocalization, and establishing TNBC xenograft models in nude mice to elucidate its mechanisms in TNBC progression. Public database analysis revealed high levels of UCHL1 in TNBC. Additional research confirmed its overexpression in TNBC tissues and cells, along with significantly increased TNBC cell proliferation, migration, and invasion associated with high UCHL1 expression. GSEA further identified UCHL1 as being predominantly enriched in pathways related to ferroptosis. UCHL1 interacted with Parkinson's disease-related glycosylation enzyme PARK7 and reduced the degradation of PARK7 protein, which was mediated through the ubiquitin-proteasome pathway. Lastly, both in vitro and in vivo studies revealed that the UCHL1-PARK7 axis fostered tumor progression in TNBC by inhibiting ferroptosis. UCHL1 deubiquitinates and stabilizes PARK7, thereby inhibiting ferroptosis and boosting tumor progression in TNBC, indicating the potential of UCHL1 and PARK7 as therapeutic targets for TNBC patients.