BACKGROUND:Sarcopenia is an age-related progressive syndrome characterized by reductions in skeletal muscle mass, decreased muscle strength, and impaired physical performance. Although sarcopenia has been correlated with elevated CVD risk, the prognostic impact of myocardial injury, measured by high‑sensitivity cardiac troponin (hs‑cTn), on extended outcomes in individuals with sarcopenia remains unclear. This study sought to determine the extent to which myocardial injury is associated with all‑cause and CVD mortality among adults with sarcopenia. METHODS:We obtained data from NHANES 1999-2004. Sarcopenia was defined as an appendicular lean mass (ALM)-to-body mass index (BMI) ratio of < 0.789 for men and < 0.512 for women. Myocardial injury was defined as any hs‑cTn assay result above the sex‑specific 99th percentile across the Roche hs‑cTnT, Abbott hs‑cTnI, Siemens hs‑cTnI, and Ortho hs‑cTnI platforms. Weighted Cox models yielded hazard ratios (HRs) and 95%CI, and Fine‑Gray models accounted for competing non‑CVD deaths. Sensitivity analyses were run to exclude baseline CVD cases or deaths within two years of enrollment. Sex, race, income, smoking, drinking, BMI, and education were used as stratification variables in subgroup analyses. RESULTS:Among 1061 sarcopenic adults, 306 had myocardial injury. These individuals were older with higher burdens of hypertension, diabetes, and prior CVD. Over median 188‑month follow‑up, the myocardial injury group showed lower survival probability (P < 0.001). After full adjustment, myocardial injury was independently associated with all‑cause (HR=1.88; 95%CI:1.41, 2.49) and CVD mortality (HR=2.19; 95%CI:1.34, 3.59). Excluding baseline CVD raised the CVD‑death HR to 2.64(1.48, 4.71); excluding 2‑year deaths yielded all‑cause HR = 1.68 (1.12, 2.53) and CVD‑death HR = 2.49 (1.33, 4.67). Subgroup analyses showed consistent effects across most strata (all P for interaction > 0.05), except for education (P for interaction=0.031). CONCLUSIONS:Myocardial injury was present in approximately 27% of sarcopenic adults and was independently associated with increased risks of all-cause and cardiovascular mortality. The associations remained robust across sensitivity analyses and were generally consistent across subgroups. These findings suggest that myocardial injury may provide prognostic information beyond conventional risk factors in adults with sarcopenia.
This pan-cancer study systematically evaluated APEX1 expression, genomic alteration status, and prognostic value across 13,270 tumors and 2544 normal tissues from TCGA and GTEx. APEX1 overexpression was prominent in bladder, breast, and colon adenocarcinomas and correlated with advanced tumor stages and survival outcomes in a cancer-type-specific manner, with unfavorable associations in selected tumor contexts and an opposite favorable association in KIRC. Low-frequency APEX1 genomic alterations require cautious interpretation and may be associated with adverse outcomes in selected tumor contexts. Statistical methods including t-tests, ANOVA, Cox regression, Benjamini-Hochberg false-discovery rate correction for cohort-wise OS analyses, and log-rank tests were used to correlate APEX1 expression or alteration status with survival outcomes. The findings suggest that APEX1 expression and low-frequency genomic alterations are associated with tumor progression and worse patient outcomes in selected cancer contexts. This study supports APEX1 as a candidate prognostic indicator requiring further validation and suggests its potential value for future clinical stratification research. The pan-cancer approach improves contextual breadth, and the large sample size adds robustness. The observed relevance of APEX1 across malignancies supports further evaluation of its value for risk stratification and treatment planning. Future prospective studies are needed to validate its clinical utility. This work contributes to the growing field of DNA repair-related biomarkers and may inform future studies of APEX1-targeted therapeutic strategies.
Ovarian non-small cell neuroendocrine carcinoma (NSCNEC) is a rare, aggressive tumor accounting for < 1% of ovarian neoplasms; all reported cases were in adults, the youngest being 18 years [3]. We report a 15-year-old girl-to our knowledge the youngest patient with primary ovarian NSCNEC in the literature. She presented with acute abdominal pain and a large cystic-solid abdominopelvic mass. Emergency fertility-sparing cytoreductive surgery established the diagnosis of NSCNEC by histopathology and immunohistochemistry. Immunohistochemistry (Fig. 1) showed neuroendocrine marker positivity (Syn, CgA, CD56, INSM1), BRG1 (+), and Inhibin-α-positive stromal cells with pericellular reticulin; CK20 and CDX2 were additionally positive, indicating intestinal-type differentiation, whereas germ cell markers (SALL4 and others) were negative. FIGO stage was IIIB. She received bleomycin-etoposide-carboplatin and remained recurrence-free at 6 months. This case indicates that ovarian NSCNEC should be considered even in adolescents, supporting calls for a global registry and standardized management.
PURPOSE:To characterize the clinicopathological spectrum of solid papillary carcinoma (SPC) in our institutional cohort and to attempt to interpret unusual findings observed during routine diagnostic workup. METHODS:We retrospectively analyzed the clinicopathological features of 20 cases of SPC from our institution. RESULTS:All 20 patients were women, aged 45-79 years (mean, 66.4 years; median, 69.5 years). Among these, 18 cases were detected by the patients themselves, one was detected during routine examination, and the remaining patient presented with bloody nipple discharge. Imaging showed that most tumors were well‑defined solid or complex cystic and solid nodules. On microscopic examination, the tumors exhibited solid nests with delicate fibrovascular cores. The tumor cells were morphologically diverse, generally showing mild atypia and rare mitotic figures. Necrosis, hemorrhage, mucin deposition, and lymphocytic infiltration were observed in the stroma. Some cases showed unusual immunohistochemical patterns, including negativity for GATA binding protein 3 (GATA3) and synaptophysin (Syn). Transcriptional repressor GATA binding protein 1 (TRPS1) and insulinoma‑associated protein 1 (INSM1) may aid in the diagnosis of such cases. Furthermore, 1 patient exhibited chromosome 17 polysomy on human epidermal growth factor receptor 2 (HER2) fluorescence in situ hybridization (FISH) analysis. Moreover, using immunohistochemistry and FISH analyses, two patients with concomitant thyroid lesions were found to demonstrate loss of phosphatase and tensin homolog (PTEN) expression, suggestive of possible Cowden syndrome. CONCLUSIONS:SPC of the breast is a rare tumor and generally carries a favorable prognosis. However, some cases may show unusual immunohistochemical expression patterns; in particular, the clinical significance of chromosome 17 polysomy detected using HER2 FISH remains unclear. In addition, occasional cases may be associated with Cowden syndrome, which warrants further investigation through genetic testing.
Background Colorectal cancer (CRC) exhibits limited response to immune checkpoint blockade (ICB) therapy. Akkermansia muciniphila has been linked to immune regulation; however, whether its administration during anti-PD-1 treatment is associated with greater antitumor activity and related metabolic and immune changes in CRC remains unclear. Methods Azoxymethane/dextran sulfate sodium (AOM/DSS)-induced and subcutaneous models were established, with A. muciniphila gavage combined with anti-PD-1 treatment. Tumor growth, short-chain fatty acids (SCFAs), and ENO1 expression were detected. Clinical data of CRC patients receiving anti-PD-1 were analyzed. Results A. muciniphila combined with anti-PD-1 alleviated weight loss, prolonged colon length, reduced colonic polyp number, and lowered histological scores. In the subcutaneous model, the anti-PD-1 plus A. muciniphila group showed reduced tumor growth, lower Ki-67/PCNA expression, and increased TUNEL-positive apoptotic cells compared with anti-PD-1 monotherapy. Intestinal acetate, propionate, and butyrate were elevated, with butyrate significantly correlating with all tumor-related indicators. In patients, responders had higher A. muciniphila abundance and butyrate concentration. Low ENO1 expression was associated with higher response rate and longer overall survival. Combined assessment of fecal A. muciniphila abundance and tumor ENO1 expression tended to separate responders from non-responders in exploratory clustering analysis. Conclusion The findings suggest that A. muciniphila administration during anti-PD-1 treatment is associated with greater antitumor activity than anti-PD-1 monotherapy. The experimental evidence supports a butyrate-associated ENO1 component contributing to tumor-cell metabolic and EMT-related changes, together with a distinct in vivo CD8⁺ T-cell immune component. These data do not establish formal synergy or a single uninterrupted causal pathway. Clinical associations require prospective validation in larger independent cohorts.
Tumor metabolic reprogramming plays a critical role in cancer progression, but how lactic acid influences tumor cell death remains incompletely understood. In this study, we investigated whether lactic acid induces ferroptosis-associated cytotoxicity and examined the underlying role of Chac1. Across multiple tumor cell lines, lactic acid reduced cell viability in a dose-dependent manner and induced cell death with both apoptotic and non-apoptotic features. These effects were not solely attributable to extracellular acidification. Transcriptomic analysis of LL2 cells revealed enrichment of ferroptosis-related transcriptional signatures, accompanied by glutathione (GSH) depletion, GPX4 downregulation, and increased oxidative stress. Treatment with Ferrostatin-1 and genetic targeting of Slc7a11 supported the involvement of ferroptosis-associated mechanisms in lactic acid-induced cytotoxicity. Mechanistically, we identified Chac1 as an important mediator linking lactic acid-induced metabolic stress to ferroptosis-associated tumor cell death, as Chac1 knockdown attenuated cytotoxicity in vitro. Furthermore, Chac1 knockdown promoted tumor growth and lung metastasis in vivo, supporting the tumor-suppressive role of Chac1 in these models. Collectively, these findings uncover a link between lactic acid and ferroptosis-associated tumor cell death, identify Chac1 as an important mediator of this response, and support a tumor-suppressive role for Chac1 in vivo.
Diabetic wounds represent a major challenge in chronic wound management, owing to a constellation of pathological features including a hyperglycemic microenvironment, persistent inflammation, impaired angiogenesis, and heightened susceptibility to infection. Conventional wound dressings, limited by their single-function design, often fall short of meeting the demands of multi-target therapy. This review systematically surveys recent advances in diabetic wound healing, with a particular focus on emerging strategies such as natural bioactive small molecules, peptide-based therapeutics, self-assembling hydrogels, and exosomes. We begin by summarizing the pathophysiological mechanisms that underlie impaired diabetic wound healing, and then discuss the pharmacological activities and delivery barriers associated with five representative natural compounds and peptide-based agents. The strengths and limitations of self-assembling hydrogels as intelligent delivery platforms are critically assessed, alongside the unique contributions of exosomes in immunomodulation, angiogenesis promotion, and facilitation of cell migration. Building on these insights, we propose a synergistic therapeutic paradigm that integrates natural molecules/peptides, self-assembling hydrogels, and exosomes. The challenges of this integrated strategy—including standardized manufacturing, regulatory approval, and clinical translation—are further analyzed, providing a reference framework for the development of multifunctional wound dressings.
Clear cell renal cell carcinoma (ccRCC), the most common RCC type, is characterized by poor prognosis and heterogeneous morphology. Recently, a prognostic ccRCC architectural grading system was proposed. Here, we evaluated the prognostic value of this architectural score. FFPE tissues were obtained from the population-based Netherlands Cohort Study. Architectural score was analyzed from digital slides (n = 333) by two independent researchers. Clinicopathological data were collected from Dutch databases. Kaplan-Meier analyses and Cox proportional hazard models were used to evaluate the association between architectural score and cause-specific survival (CSS), and models were compared with ROC curves, AICs and c-statistics. Architectural score was associated with all clinicopathological variables, besides age at diagnosis and sex, and was associated with CSS in univariate analyses (HRscore 3=2.70, HRscore 4=4.06, both P < 0.001). However, in multivariate analyses (including age at diagnosis, sex, WHO/ISUP grade, TNM stage and tumor size), architectural score did not predict survival. Model fit was similar for models containing the architectural score and the 2022 WHO/ISUP grade (c-statistics: 0.69-0.73). Nevertheless, the architectural score was possibly found to be a significant predictor of survival in lower-grade WHO/ISUP tumors in post hoc analyses (P = 0.008), but not in higher grade WHO/ISUP tumors. Although architectural scoring could be used to identify patients with a poor CSS, these effects are not independent of other established prognostic factors. However, architectural scoring might identify a high-risk subgroup that are low-grade WHO/ISUP tumors and might further refine ccRCC risk-stratification, yet, more research is needed to confirm this exploratory finding in larger cohorts.
Exertional heatstroke (EHS) is a life-threatening medical condition with a high mortality rate, characterized by dysfunction of the central nervous system, including memory impairment. Astrocytes have been reported to be closely related to learning and memory process. However, the role of astrocytes in EHS has not been elucidated. In this study, an EHS mouse model was established to recapitulate the physical state of human in severe environment of high temperature and humidity. EHS mice showed significant memory decline in novel location recognition and shuttle box tests. To investigate the underlying mechanisms, RNA sequencing of the hippocampal tissue was performed, and the results indicated that astrocytes and neuroinflammation-related signaling pathways were activated in EHS mice. The activation of astrocytes was confirmed by the increased protein and mRNA levels of GFAP. The production of pro-inflammatory factors, including IL-6, IL-1βand TNF-α, was also increased. Furthermore, we used fluoxetine (Flu) to suppress astrocyte activation. Flu significantly improved learning and memory impairment of EHS mice and reversed the upregulation of GFAP. Therefore, our data suggest that EHS triggers hippocampal astrocyte activation accompanied by a astrogliosis-associated neuroinflammatory response with elevated pro-inflammatory cytokine expression, contributing to learning and memory impairment in mice. Flu serves as a potential therapeutic drug in EHS-induced learning and memory disorder.
Metabolic bone disease results from the imbalance between bone formation and bone resorption and has core pathological features of gradual bone mass loss, damaged bone microstructure and bone marrow adipose infiltration. Ferroptosis is iron-dependent regulated cell death driven by lipid peroxidation and plays a key regulatory role in bone metabolic homeostasis. Peroxisome proliferator-activated receptor γ (PPARγ) acts as a core link among ferroptosis, lipid metabolism and bone cell fate. PPARγ induces ferroptosis in osteoblasts and bone marrow mesenchymal stem cells (BMSCs) by regulating antioxidant defense, lipid metabolism and iron homeostasis and produces two different effects on osteoclasts based on PPARγ activation level and local bone microenvironment. This mechanism causes reduced osteoblast numbers, abnormal osteoclast function, increased empty osteocyte lacunae, thinner bone trabeculae, accumulated lipid peroxidation products, increased iron deposition and enhanced bone marrow adipogenesis at the histopathological level. The PPARγ-ferroptosis axis participates in the development of osteoporosis, osteonecrosis, inflammatory bone diseases and iron overload-related bone diseases. This pathway connects with inflammation and oxidative stress and promotes continuous disease progression. This review fully explains the structure and biological functions of PPARγ and its pathological roles in various bone diseases. This review also summarizes PPARγ antagonists, ferroptosis inhibitors, natural products, bone-targeted drug delivery systems and gut microbiota regulation methods. These results provide theoretical support for precise diagnosis, new drug development and clinical translation of metabolic bone disease treatment.
Colorectal cancer (CRC) ranks as the third most prevalent cancer worldwide, with nearly 2 million new cases diagnosed annually. Patients with solid tumors are widely recognized to often exhibit abnormal activation of the coagulation system, leading to a high prevalence of thromboembolism (VTE). Microparticles (MPs) are a subset of extracellular vehicles (EVs) that differ from exosomes and apoptotic bodies primarily in their size, composition, and mechanisms of formation and release. MPs are integral to tightly controlled biological processes, including hemostasis, inflammation, and protein transfer. The impact of platelet-tumor interactions varies with the environment-either local tissue or circulation-leading to either inhibition or promotion of cancer progression. Also, Tumor-derived microvesicles (TMVs) play an essential role in tumor progression by affecting the biological functions of immune cells such as lymphocytes, monocytes, and macrophages. This interaction is particularly significant in CRC, where macrophages contribute to tissue recovery processes. It is proposed that cancer patients experiencing VTE exhibited significantly greater mean TF (+) MPs activity compared to those without VTE. PS-positive platelets and MPs have a role in the hypercoagulable state of CRC patients and may serve as promising therapeutic targets to prevent coagulation in this population. Circulating MPs, especially fibrin-bearing MPs, may serve as novel biomarkers for predicting thrombo-embolic complications and poorer prognosis in cancer patients. In this review article, we have explored various MPs in CRC, especially those are related to hypercoagulation.
Hepatic ischemia-reperfusion injury is a common clinical challenge in liver surgery, involving complex mechanisms of cell death in its pathological process. Conventional single-target intervention strategies have shown limited efficacy, highlighting the need to explore novel regulatory approaches from a systemic perspective. In recent years, a novel integrated programmed cell death modality-PANoptosis-has emerged as a promising concept, offering new insights into untangling the intricate mechanisms of hepatic ischemia-reperfusion injury by synergistically activating molecular pathways of apoptosis, pyroptosis, and necroptosis. This review systematically summarizes the molecular components and signaling regulatory networks of PANoptosis, as well as its activation mechanisms in hepatic ischemia-reperfusion injury. It particularly elaborates on its pathological effects in both hepatocytes and non-parenchymal cells, such as hepatic sinusoidal endothelial cells and Kupffer cells, and analyzes the crosstalk and synergistic interactions between PANoptosis and other forms of cell death. Studies have revealed that metabolic stress, oxidative stress, and the release of damage-associated molecular patterns can induce mitochondrial dysfunction, leading to the coordinated activation of multiple pathways that exacerbate liver injury and amplify inflammation. Both animal models and cellular experiments have confirmed that specific knock out of key molecules or the use of small-molecule inhibitors can significantly mitigate liver damage. Furthermore, natural products, gene-editing technologies, and preconditioning strategies have also demonstrated considerable interventional potential. However, current research still faces limitations, including insufficient mechanistic depth, a disconnect between animal models and clinical relevance, and inadequate understanding of the interactive regulation among multiple cell death modalities. Future studies should focus on elucidating cell type-specific mechanisms, developing humanized models, integrating multi-omics analyses, and promoting the clinical translation of targeted therapeutics. These efforts are expected to facilitate a shift from single-target interventions toward multidimensional and systemic treatment strategies, thereby providing theoretical support and practical pathways for improving outcomes in patients undergoing liver surgery.
BACKGROUND:Tumor-associated macrophages (TAMs), as core components of the triple-negative breast cancer (TNBC) tumor microenvironment (TME), can promote tumor progression. Ferroptosis has been shown to be involved in TNBC progression, but its regulatory mechanisms in TNBC TAMs remain incompletely understood. METHODS:Clinical samples of TNBC were collected, and in vitro co-culture systems and BC xenograft models were established. By combining the results of the TCGA-BRCA and METABRIC transcriptomic cohort analyses, the expression characteristics and immune associations of ACOD1 were examined. Functional exploration was conducted through CCK-8, EdU, and colony formation assays and the detection of ferroptosis-related indicators. Molecular mechanisms were investigated using co-immunoprecipitation (Co-IP), CETSA, DARTS, SPR, and molecular docking. RESULTS:ACOD1 expression was upregulated in immune-infiltrated subtypes, such as Basal-like/TNBC and HER2-enriched subtypes and significantly positively correlated with the infiltration of myeloid immune cells, including macrophages. Further results revealed that ACOD1 is highly expressed in TNBC TAMs and is driven by TME signals, independent of the classical M2 polarization pathway. The knockdown of ACOD1 in TAMs inhibited MDA-MB-231 cell proliferation and in vivo tumor growth and reduced ferroptosis resistance in TAMs. Mechanistically, ACOD1 knockdown did not affect KEAP1 expression but did reduce the expression of NRF2 and its downstream target genes HO-1 and NQO1, decreased NRF2 nuclear translocation, and increased KEAP1-NRF2 binding. Knockdown of KEAP1 or overexpression of NRF2 enhanced ferroptosis resistance. Additionally, ACOD1 knockdown decreased itaconate (ITA) levels in TAMs. The ITA derivative 4-OI was directly bound to KEAP1, weakened the KEAP1-NRF2 interaction, inhibited NRF2 ubiquitination, and stabilized NRF2 expression. CONCLUSION:ACOD1, through its enzymatic product ITA, promotes ITA binding to KEAP1, which inhibits the KEAP1-NRF2 interaction and thus activates NRF2-mediated antioxidant and ferroptosis resistance responses in TAMs, promoting TNBC progression.
Therapeutic resistance remains a major obstacle in cancer treatment and limits the durability of immunotherapy, chemotherapy, and targeted therapy. Tumor-associated macrophages (TAMs) contribute to resistance through spatially and functionally heterogeneous programs shaped by hypoxia, vascular niches, metabolic stress, tumor-derived signals, and therapy-induced inflammation. Chronic IFN-γ exposure can also promote adaptive resistance through checkpoint induction, altered antigen presentation, suppressive feedback signaling, metabolic rewiring, and epigenetic remodeling. This review examines how TAM heterogeneity and IFN-γ signaling intersect to support therapy evasion, with emphasis on macrophage niches, phagocytosis resistance, lactate-associated epigenetic regulation, and clinically relevant feedback loops. We also discuss why several TAM-directed strategies, including CSF1R inhibition, have shown stronger activity in preclinical models than in clinical trials. Finally, we evaluate emerging approaches such as macrophage reprogramming, CD47/SIRPα blockade, CAR-macrophage engineering, and biomarker-guided combination therapy. A clearer understanding of TAM states, spatial context, and IFN-γ dynamics may improve patient stratification and support more rational translational strategies to overcome therapeutic resistance.
BACKGROUND:Hepatocellular carcinoma (HCC) has a poor prognosis and lacks robust, generalizable stratification markers and interpretable therapeutic targets. R-loop dysregulation can induce replication stress and DNA damage, but its clinical relevance and driver cell states in HCC remain unclear. METHODS:Multi-cohort public datasets (n = 2031) integrating bulk, immunotherapy, single-cell, spatial, and proteomic resources were analyzed. R-loop scores, consensus subtypes, and a WGCNA/machine-learning prognostic signature were established and interpreted by SHAP, with experimental validation of KIF2A and MK-1775 sensitivity. RESULTS:The R-loop score was significantly elevated in HCC tumors, increased with clinical stage, and consistently predicted poorer overall survival across cohorts. Three reproducible R-loop molecular subtypes showed distinct prognostic and clinicopathological patterns; the unfavorable subtype was enriched for cell-cycle, DNA replication, and repair programs. A seven-gene R-loop risk signature showed stable external prognostic performance and improved prediction beyond TNM stage and AFP. High R-loop activity was associated with immune checkpoint expression, T-cell exhaustion, and reduced benefit from immune checkpoint blockade. Multi-scale analyses localized the high-risk signal to a reproducible KIF2A-positive proliferative tumor-cell state that correlated with R-loop activity, hypoxic malignant spatial niches, immune-exhausted features, and poor prognosis. KIF2A was the top SHAP-ranked contributor and was consistently upregulated across transcriptomic, proteomic, single-cell, spatial, and histological layers. Stable KIF2A knockdown reduced CCNB2/CDC20 expression, suppressed colony formation, and inhibited xenograft growth. KIF2A-high HCC cells showed greater MK-1775 sensitivity. CONCLUSIONS:R-loop-associated programs define a clinically relevant prognostic axis in HCC, with KIF2A-positive proliferative tumor cells representing a key high-risk cellular source and potential therapeutic vulnerability.
BACKGROUND:Lung adenocarcinoma (LUAD) is a malignant tumor characterized by high invasiveness and poor prognosis. Although phospholipid phosphatase 3 (PLPP3) is downregulated in LUAD, its functional mechanisms in this cancer remain poorly understood. METHODS:The expression levels of PLPP3 and membrane-associated RING-CH-1 (MARCH1) in LUAD tissues and cells were evaluated using the Gene Expression Profile Interactive Analysis (GEPIA) database, Gene Expression Omnibus (GEO), quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot techniques. The roles of MARCH1 and PLPP3 in LUAD were investigated through functional assays (colony formation, flow cytometry, wound healing assay, Transwell assay, nude mouse xenograft model, immunohistochemistry (IHC), Fe²⁺ detection, malondialdehyde (MDA) detection, glutathione (GSH) detection, lipid reactive oxygen species (ROS) detection, and cell counting kit-8 (CCK-8) assay). Mechanistic studies, including co-immunoprecipitation (Co-IP), ubiquitination assay, and cycloheximide (CHX) chase experiments, were conducted to elucidate their potential regulatory mechanisms. RESULTS:PLPP3 was downregulated in LUAD. PLPP3 suppressed cell proliferation, promoted apoptosis, inhibited migration and invasion in LUAD cells, and impaired tumor growth in vivo. In addition, PLPP3 downregulated glutathione peroxidase 4 (GPX4) and upregulated acyl-coA synthetase long chain family member 4 (ACSL4), elevated Fe²+ and MDA levels, reduced GSH levels, and increased lipid ROS levels. These effects could be reversed by ferroptosis inhibitor Ferrostatin‑1 (Fer‑1) and Liproxstatin-1 (Lip-1). Furthermore, MARCH1 promoted the K48- and K63-linked polyubiquitination of PLPP3, thereby leading to the rapid proteasomal degradation of PLPP3. Rescue experiments demonstrated that MARCH1 enhanced the malignant phenotypes of LUAD cells, inhibited ferroptosis, and promoted tumor progression by suppressing PLPP3 expression. CONCLUSION:MARCH1 promotes the malignant progression of LUAD by regulating the ubiquitination of PLPP3, highlighting its potential as a therapeutic target.
