BACKGROUND Chemoresistance significantly limits the therapeutic efficacy of neoadjuvant chemotherapy (NACT) in advanced gastric cancer (AGC). There is an urgent need to identify robust biomarkers predictive of NACT response and to elucidate the molecular mechanisms that drive resistance. In this study, we systematically assess whether intercellular adhesion molecule 2 (ICAM2 ) predicts NACT response in patients with AGC and delineate its mechanistic role in chemoresistance. AIM To investigate the predictive significance and mechanistic role of ICAM2 in mediating 5-fluorouracil (5-FU) resistance in gastric cancer (GC). METHODS Real-time PCR, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry were conducted to assess alterations in ICAM2 expression between 5-FU-sensitive and -resistant GC cells as well as in AGC patient samples. Cytotoxicity assays, colony formation, flow cytometry, analyses of apoptosis-related proteins, and xenograft experiments were employed to elucidate the role of ICAM2 in mediating chemoresistance. The mechanism underlying ICAM2 -mediated chemoresistance was further explored through RNA sequencing (RNA-seq), nuclear-cytosolic fractionation, co-immunoprecipitation, luciferase reporter, and chromatin immunoprecipitation assays. RESULTS Low ICAM2 expression correlated significantly with poor NACT response, advanced tumor stage, worse differentiation, and reduced overall survival and disease-free survival in AGC patients. Pre-NACT serum ICAM2 demonstrated high predictive accuracy (area under the curve = 0.876) in discriminating chemotherapy responders from non-responders. Mechanistically, ICAM2 knockdown conferred 5-FU resistance through two intertwined processes: Inhibition of caspase-dependent apoptosis and promotion of immunosuppressive M2 macrophage polarization within the tumor microenvironment. At the molecular level, loss of ICAM2 activated the TGF-β/Smad pathway, leading to transcription factor SP1-mediated pleiotrophin (PTN) upregulation. Elevated PTN further enhanced GC cell survival and may contribute to M2 macrophage polarization, thereby amplifying chemoresistance. Importantly, targeted inhibition of TGF-β signaling reversed ICAM2-associated chemoresistance in both cell culture and xenograft models. CONCLUSION Our study highlights the clinical impact of ICAM2 downregulation predicting poor outcome and NACT response in AGC patients, and reveals a novel ICAM2/TGF-β/Smad/SP1/PTN signaling mediating 5-FU resistance in GC.

Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by epithelial-mesenchymal transition (EMT) as a key pathological feature. The molecular mechanism of EMT is not fully understood. Hence, the current study aimed to investigate the pathogenesis of EMT, which focus on the function of Epithelial Splicing Regulatory Protein 1 (ESRP1) in regulating EMT. Methods The present study utilized bleomycin (BLM) to establish mouse models of IPF. Then, single-cell RNA sequencing (scRNA-seq) of entire lung tissue was employed to delineate transcriptional alterations in epithelial cells and to nominate prospective regulators of EMT. The target gene was subsequently validated in vivo and in vitro by qPCR, western blot, and immunofluorescence. Furthermore, an EMT model was established in TGF-β1–treated MLE-12 alveolar epithelial cells. Lentivirus or siRNA was hired to modulate the expression of target gene and elucidate its mechanistic contribution to EMT. Results ScRNA-seq revealed marked up-regulation of the ESRP1 in alveolar epithelial cells compared with PBS-treated controls. Subsequent mechanistic interrogation in primary and MLE-12 alveolar epithelial cells demonstrated that knockdown of ESRP1 suppressed, whereas its overexpression potentiated, the expression of Epac, Rap1a, and N-cad which were key effectors of EMT. Importantly, Co-IP (Co-Immunoprecipitation) showed that there was interaction between ESRP1, Epac, and Rap1a. Silencing of either Epac or Rap1a did not reciprocally alter ESRP1 expression, confirming an upstream regulatory hierarchy. Conclusion Our findings demonstrate that ESRP1 upregulation in alveolar epithelial cells drives IPF progression by promoting EMT via the Epac–Rap1a axis.

Dengue fever continues to exert significant global impact, affecting populations worldwide with considerable public health and economic consequences. There is no antiviral drug for dengue. This study focuses on hypericin, a naturally occurring compound from Hypericum perforatum L. whose anti-dengue properties have been underexplored. We systematically examined its antiviral efficacy against dengue virus (DENV), revealing strong inhibitory effects and clarifying its precise antiviral mechanism. The study assessed the efficacy of hypericin against DENV using various scientific methods like plaque assays and Western blotting. We looked into its antiviral mechanism. We used a time-of-addition approach during our research. Moreover, the basic mechanisms involved were studied through molecular docking, surface plasmon resonance (SPR), and co-immunoprecipitation (Co-IP). This study demonstrated that hypericin exhibits broad-spectrum antiviral activity against DENV-2 in cell lines derived from multiple species. In time-of-addition experiments, it showed inhibitory effects under co-treatment, direct virucidal, and post-treatment conditions. Crucially, hypericin primarily blocked viral attachment and entry stages, thereby effectively reducing intracellular viral load. Mechanistic investigations revealed a interaction between hypericin and the E protein, evidenced by a computational docking score of -7.0kcal/mol and an experimental SPR-derived Kd of 7.18 µM. Furthermore, Co-IP assays demonstrated that hypericin competitively blocks the association between the E protein and its cellular receptor, HSP70. As per these findings, the E protein was seen to be a target of hypericin with an antiviral activity against DENV-2 at multiple stages by limiting viral adsorption and viral entry projecting a molecular basis for the candidate molecule as a possible anti-dengue agent.

Preeclampsia is a severe hypertensive disorder of pregnancy associated with low SIRT1 (sirtuin 1) levels in trophoblasts. Single-cell sequencing showed abnormal activation of trophoblast Rarres2 (retinoic acid receptor responder 2) and macrophage Cmklr1 (chemokine-like receptor 1) at the maternal-fetal interface in systemic Sirt1 heterozygous knockout mice. This study investigated how low SIRT1 in trophoblasts increases RARRES2 expression, affecting macrophage polarization and preeclampsia pathogenesis. We conducted coculture experiments to analyze trophoblast RARRES2 and macrophage CMKLR1 interactions, performed luciferase and chromatin immunoprecipitation assays to validate transcription factors for RARRES2 in trophoblasts, and utilized mass spectrometry and immunoprecipitation to identify transcriptional coregulators. cKO (trophoblast-specific Sirt1 knockout) mice were generated and treated with Rarres2 knockout or progesterone supplementation to validate the role of the SIRT1/RARRES2 axis in preeclampsia pathogenesis and prevention by progesterone. Finally, we measured RARRES2 and SIRT1 levels in the plasma of patients with preeclampsia. Low-SIRT1 expression in trophoblasts promoted M1-type macrophage polarization and inhibited trophoblast invasion, mediated by the RARRES2-CMKLR1 interaction. SIRT1 regulated RARRES2 expression in trophoblasts by recruiting NCOR2 (nuclear receptor corepressor 2). cKO mice showed preeclampsia-like symptoms and RARRES2-CMKLR1 activation at the maternal-fetal interface, which were reversed by Rarres2 knockout or progesterone supplementation. Notably, RARRES2 levels were higher and were a risk factor, whereas SIRT1 levels were lower and were a protective factor for preeclampsia in early pregnancy. This study highlights SIRT1's potential role in regulating abnormal trophoblast-macrophage interactions at the maternal-fetal interface in preeclampsia and offers a new strategy for its early prediction and prevention.

Ginseng's prolonged development renders it susceptible to environmental stresses. Late embryogenesis abundant (LEA) proteins are essential for plant resistance to abiotic stress. Our previous study demonstrated that PgLEA2-50, a member of the LEA protein family, plays a significant role in stress resistance. In this study, we employed IP-MS, bioinformatics, and molecular interaction assays to investigate the mechanisms underlying its stress resistance. PgLEA2-50 formed complex networks with multiple interacting proteins, which were enriched in stress-related processes such as gibberellin (GA) signal transduction, saponin biosynthesis, and the oxidative stress response. Transcriptome analysis revealed that its interacting targets exhibited significant responses to abiotic stress at the transcriptional level. An investigation of the DELLA protein PgRGA4 showed that it was down-regulated following GA induction, with its transcriptional activity inhibited under stress conditions. PgRGA4 was found to be localized in both the nucleus and cytoplasm, and co-immunoprecipitation (CO-IP) confirmed its interaction with PgLEA2-50, suggesting that PgLEA2-50 indirectly regulates GA-mediated stress resistance. This study provides a ginseng-specific case for the role of LEA proteins in stress resistance and identifies a novel gene target for molecular breeding in medicinal plants.

Protein phosphorylation and ubiquitination play central roles in signal transduction. SnRK1 is a key kinase that mediates plant responses to environmental cues. From a wild soybean cDNA library, we identified GsSRF2, which encodes a RING-domain E3 ligase that interacts with GsSnRK1. GsSRF2 is predominantly expressed in roots and responds dynamically to salt stress. BiFC, pull-down, and co-IP assays this interaction in the cytoplasm and at the plasma membrane. Biochemical analyses revealed that GsSnRK1 phosphorylates GsSRF2 at Thr514. GnSnRK1-mediated phosphorylation enhanced GsSRF2 ubiquitination and promoted its proteasomal degradation. Coexpression assays in soybean hairy roots demonstrated that the GsSnRK1-GsSRF2 module significantly improved salt tolerance, whereas the GsSnRK1-GsSRF2(T514A) and kinase-dead GsSnRK1(K49M)-GsSRF2 modules reduced salt resistance in composite plants. Together, these results indicate that GsSnRK1 positively regulates soybean salt tolerance by modulating GsSRF2 ligase activity and protein stability, providing valuable genetic resources for crop improvement.

LDB1 represses fetal hemoglobin expression by enhancing BCL11A transcription.

Cyclin L1 (CCNL1) is highly expressed in multiple cancer types and has been linked to poor prognosis. However, the expression pattern of CCNL1 in breast cancer and its specific role in regulating breast cancer progression remain largely unknown. This study used cell and molecular biology techniques to examine how CCNL1 regulates the proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) of breast cancer cells. The applied methods encompassed plasmid transfection, Transwell assay, wound-healing assay, Western blot analysis, co-immunoprecipitation (Co-IP), and rescue assay. For the analysis of CCNL1-related factors and pathways, bioinformatics platforms including Metascape and HURI were also employed. CCNL1 is highly expressed in breast cancer cells and is associated with a poor prognosis. CCNL1 overexpression increased breast cancer cell invasion and migration and accelerated proliferation. Overexpression of CCNL1 was found to upregulate the mesenchymal marker Vimentin and downregulate the epithelial marker E-cadherin expression. There is close relationship between CCNL1, the NF-κB and PI3K/AKT signaling pathways. The direct interaction is verified between CCNL1 and DVL3 by Co-IP, indicating a negative correlation between the two proteins. CCNL1 overexpression affects breast cancer cells' paclitaxel sensitivity through the PI3K/AKT pathway. CCNL1 activates the NF-κB signaling pathway through its interaction with DVL3; additionally, it promotes the PI3K/AKT pathway. Together, these two mechanisms enable CCNL1 to exert a regulatory role in the progression of breast cancer.

The concerted action of regulatory RNA and RNA binding proteins (RBPs) provide cells with highly versatile and transient tools to fine tune gene expression in a broad variety of cellular systems (Unfried and Ulitsky 2022, Hentze et al. 2018, Suzuki et al. 2018). In this work, we explore the function of a specific interaction between PTBP1 and the cytoplasmic long non-coding RNA (lncRNA) CyCoNP, highly expressed in neural progenitors (Desideri et al. 2024), in which the RBP regulates the abundance of the lncRNA by a miRNA-mediated mechanism. PTBP1 is a well-known splicing regulator, although limited and peculiar examples of its involvement in other cellular processes, such as IRES-dependent translation and miRNA recognition of target RNAs, have been described (Dorn et al. 2023, Kim et al. 2021). We have recently characterized CyCoNP lncRNA as a regulator of NCAM1, which acts through a mechanism that involves direct RNA-RNA interaction with NCAM1 mRNA, balancing the availability and the localization of miR-4492 in its vicinity (Desideri et al. 2024). Here we expand the repertoire of molecular players acting in this circuitry by describing a direct interaction between PTBP1 and CyCoNP lncRNA. Through endogenous RNA purification, protein immunoprecipitation and exploiting CyCoNP mutant constructs we found that PTBP1, when interacting with CyCoNP, hampers miR-4492 binding to the lncRNA and in turn impedes its regulation on NCAM1 mRNA. This work aims to expand the biochemical characterization of regulatory networks relying on RBPs and their cognate target RNAs, highlighting the relevance of the analysis of the subcellular environment for each case of study.

Postoperative cognitive dysfunction (POCD) is a common and serious complication in older adult patients. While the tyrosine kinase ABL1 has been implicated in neurodegenerative diseases, its specific role in POCD remains unexplored. This study aims to investigate whether ABL1 influences POCD in aged mice by regulating microglial autophagy and neuroinflammation via the mTOR/ULK1 pathway. An aged mouse model of POCD was established, and ABL1 silencing and 3-Methyladenine (3-MA) were used to intervene in mice. The Novel Object Recognition Test (NORT) assessment and water maze experiment were conducted. qRT-PCR quantified the mRNA levels of inflammatory cytokines, hippocampal damage was assessed by immunofluorescence, and western blot analyzed the protein expression of autophagy-related genes and the mTOR/ULK1 pathway. Co-Immunoprecipitation (CO-IP) was used to detect the binding of ABL1 to mTOR. In vitro experiments used microglial cells, where ABL1 silencing and rapamycin (Rapa) were used to construct a cellular model and conduct relevant cell experiments. ABL1 silencing or 3-MA rescued cognitive deficits in aged POCD mice, concurrently mitigating neuroinflammation, microglial activation, and aberrant autophagy in the hippocampus. We established ABL1 as a direct binding partner of mTOR. Silencing ABL1 activated the mTOR pathway, leading to ULK1 inhibition and suppression of autophagic activity. Consistent with these in vivo results, ABL1 knockdown in microglia attenuated pro-inflammatory responses, inhibited autophagy, and conferred protection against neuronal damage. ABL1 exacerbates POCD in aged mice by promoting microglial autophagy and neuroinflammation through the mTOR/ULK1 signaling pathway. Targeted inhibition of ABL1 may represent a novel therapeutic strategy for preventing or treating POCD.

PpCML14 confers drought and salinity tolerance by interacting with PpGMP1 for improved AsA biosynthesis and upregulating antioxidant enzyme activities, proline accumulation, and stress-responsive genes. Calcium is a universal second messenger in plant cells, regulating plant growth, development, and responses to environmental stresses. Calmodulin-like proteins (CMLs) are one of the Ca2+ sensors or Ca2+-binding proteins. However, the functions of lots of members in CML family remain largely unknown. A PpCML14 from the native Kentucky bluegrass (Poa pratensis L.) was examined to regulate drought and salinity tolerance in the present study. PpCML14 is highly expressed in roots, and its overexpression in rice resulted in increased drought and salinity tolerance, with promoted activities of antioxidant enzymes, including superoxide dismutase, catalase, and ascorbate peroxidase, proline accumulation, and expressions of ABA-dependent and ABA-independent stress-responsive genes. Additionally, PpGMP1 (GDP-D-mannose pyrophosphorylase 1), a key enzyme for ascorbic acid (AsA) biosynthesis, was identified as interacting with PpCML14 based on screening of cDNA library and further confirmation using the methods of yeast-two-hybridization, firefly luciferase complementation imaging (LCI), pull-down, and co-immunoprecipitation (Co-IP). Overexpression of PpGMP1 in rice led to increased drought and salinity tolerance. AsA levels and AsA redox were higher, but reactive oxygen species (ROS) accumulation was lower in both PpGMP1- and PpCML14-overexpressing rice lines under drought and salinity conditions compared with wild-type plants. The results indicated that AsA biosynthesis is regulated by the PpCML14-PpGMP1 module. AsA is an important antioxidant for scavenging ROS. It is suggested that PpCML14 confers drought and salinity tolerance through upregulating antioxidant enzyme activities, proline accumulation, and stress--responsive genes, and by activating PpGMP1 to improve AsA biosynthesis.

KLF2 interacts with AP-1 to negatively affect osteoclast differentiation and activity.

Reprogramming of differentiated root cortical cells into proliferative stem cells is the prerequisite for legume nodule organogenesis, yet the molecular trigger that confers stem-cell identity upon these cortical cells remains elusive. Here we demonstrate that, in soybean (Glycine max), the canonical root stem-cell regulator WUSCHEL-RELATED HOMEOBOX gene WOX5 is activated by rhizobia specifically in cortical cells that will give rise to nodule primordia. CRISPR/Cas9-mediated knockout of the three WOX5 homologs, wox5abc mutants reduced nodule number and attenuated nitrogenase activity, attributable to a decrease in primordium density rather than impaired rhizobia infection. Promoter dissection identified a 442 bp legume-specific promoter fragment within the WOX5a promoter that is both necessary and sufficient for primordium-specific expression. Chromatin immunoprecipitation and dual-luciferase assays revealed that this promoter fragment is directly bound by the symbiosis-responsive transcription factor NF-YAc to activate expression of WOX5a. Loss of NF-YAc phenocopied wox5abc, and NF-YAc overexpression failed to rescue nodulation in wox5abc mutants. Collectively, our findings reveal that NF-YAc-mediated activation of WOX5 initiates a de novo stem-cell niche in root cortical cells, providing the critical developmental trigger for nodule primordium initiation in soybean.

Mitophagy dysfunction is a critical contributor to retinal pigment epithelial (RPE) cell damage during the progression of retinal degenerative diseases, including age-related macular degeneration (AMD). In this study, we investigated the effects of paeoniflorin (PF) on mitophagy in RPE cells, with a particular focus on the CUL3/LKB1/AMPK/ULK1 signaling pathway. ARPE-19 cells were treated with different concentrations of PF to evaluate cytotoxicity, and its protective effects were further examined in H₂O₂-induced oxidative stress models in vitro and in sodium iodate (NaIO₃)-induced RPE injury models in vivo. Protein levels of CUL3, apoptosis-related factors, mitophagy markers, and components of the LKB1/AMPK/ULK1 pathway were assessed by western blotting, and mitophagy was visualized using MitoTracker labeling. Cycloheximide (CHX) and coimmunoprecipitation (Co-IP) assays were performed to analyze the interaction between CUL3 and LKB1. PF treatment enhanced mitophagy in H₂O₂-stimulated ARPE-19 cells, whereas Parkin knockdown markedly attenuated this effect. In oxidatively damaged cells, PF promoted AMPK and ULK1 phosphorylation, increased mitophagy-associated protein expression, and alleviated mitochondrial dysfunction; these protective effects were abolished by pharmacological inhibition of AMPK or ULK1. In addition, CUL3 overexpression significantly attenuated PF-induced mitophagy activation and reduced PF-associated phosphorylation of LKB1, AMPK, and ULK1. Mechanistically, PF downregulated CUL3 expression, while CUL3 promoted the ubiquitination and degradation of LKB1. Silencing CUL3 induced mitophagy in H₂O₂-treated cells, whereas concurrent knockdown of CUL3 and LKB1 abolished this effect. In vivo, PF mitigated RPE cell loss, enhanced mitophagy, and activated the CUL3/LKB1/AMPK/ULK1 signaling pathway in the retinal tissues of NaIO₃-induced mice. Collectively, these findings indicate that PF protects against RPE injury in an NaIO₃-induced AMD-like model by downregulating CUL3 expression and activating LKB1/AMPK/ULK1-mediated mitophagy.

MD2 mediates COPD pathogenesis by inducing airway inflammation and ferroptosis through the TLR4/MyD88 pathway.

Ginsenoside Rg3 alleviates allergic rhinitis by regulating NLRP3-mediated inflammatory response and pyroptosis through SIRT6.

WSSV promotes its replication by inhibiting Dorsal activation via CypA in crayfish.

Paclitaxel is a frequently employed chemotherapeutic agent for nasopharyngeal carcinoma (NPC) patients, and tumor cell resistance to paclitaxel poses a significant challenge to NPC treatment. This study investigated the impact and potential mechanisms of folate-receptor 1 (FOLR1) on paclitaxel resistance in NPC cells. Levels of FOLR1 in NPC tissues and cells were measured using RT-qPCR. Protein expression was analyzed by Western blot. IC50 of paclitaxel-treated NPC cells was assessed by CCK-8. EdU and Colony formation assay detected cell proliferation. Apoptosis and pyroptosis were evaluated utilizing flow cytometry. Expression and localization of ITCH and FOLR1 were detected by immunofluorescence staining. Interaction between ITCH and FOLR1 was tested by co-immunoprecipitation (Co-IP). The immunoprecipitation assay evaluated FOLR1 ubiquitination levels. An NPC xenograft model was constructed in nude mice. FOLR1 was overexpressed in NPC and correlates with a poor prognosis in NPC patients. Low levels of cell pyroptosis and elevated FOLR1 expression were strongly associated with paclitaxel resistance in NPC. Knockdown of FOLR1 reduced the chemoresistance of 5-8 F/paclitaxel cells to paclitaxel. ITCH was associated with FOLR1 and enhanced its degradation through ubiquitination. ITCH reduced paclitaxel resistance in NPC cells via downregulation of FOLR1. FOLR1 increased resistance to paclitaxel by suppressing pyroptosis in NPC through an NLRP3-dependent mechanism. FOLR1 inhibited pyroptosis by inhibiting the mTOR pathway and promoting autophagy. Lowering FOLR1 expression suppressed tumor growth and boosted paclitaxel sensitivity in mice. FOLR1 plays a significant role in promoting chemoresistance of NPC cells to paclitaxel through NLRP3 signaling.

A pivotal strategy in immuno-oncology is the initiation and modulation of adaptive immune responses. Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), known for its role in protein homeostasis and functionality, is implicated in tumorigenesis. However, its part in the antitumor immunity mediated by CD8+ T cells in lung adenocarcinoma (LUAD) is not yet clear. We harnessed bioinformatics to evaluate the clinical relevance of UCHL1 in LUAD, performed IHC to detect the expression of UCHL1 in LUAD tissue, and utilised qPCR to assess UCHL1 levels in LUAD cells, exploring its correlation with the presence of CD8+ T cells. The effects of UCHL1 on CD8+ T cell vigour have been investigated using lactate dehydrogenase and enzyme-linked immunosorbent assay kits, as well as flow cytometry. The contribution of UCHL1 to ferroptosis was examined with ferrous ion and manganese dioxide assay kits, alongside western blot. Furthermore, we utilised bioinformatics software UbiBrowser and Hdock, in conjunction with co-immunoprecipitation (Co-IP), immunofluorescence, and IP methods, to dissect the interaction between UCHL1 and FHL2. Rescue experiments further clarified the mechanism by which UCHL1 modulates FHL2 in tumour immunity. Invivo experiments confirmed the promoting effect of UCHL1 on tumour growth. Elevated UCHL1 levels in LUAD tissues and cells were observed. Dampening UCHL1 triggered ferroptosis in LUAD cells, which in turn ramped up CD8+ T cell activity and enhanced their tumour-killing potential. Mechanistically, UCHL1 was shown to deubiquitinate the downstream factor FHL2, and knocking down FHL2 could counteract the immunosuppressive effects induced by high UCHL1 levels on CD8+ T cells. UCHL1 inhibitor LDN57444 significantly inhibited tumour growth in mice. Therapies aimed at the UCHL1/FHL2 axis could be effectively paired with immunotherapies, opening new avenues in cancer treatment strategies.

Brain metastasis (BM) is a leading cause of mortality in non-small-cell lung cancer (NSCLC). The abnormal expression and regulation of circular RNA (circRNA) is involved in the pathogenesis of various tumors. However, the involvement of circRNAs in BM of NSCLC remains to be elucidated. In this study, we established an in vitro blood-brain barrier (BBB) model using BM NSCLC cell lines H2030-BrM3 and PC9-BrM3. We investigated the impact of circ_phosphatidic acid phosphatase type 2 domain containing 1A (PPAPDC1A) on BM of NSCLC in vitro. The interaction between circ_PPAPDC1A and sparc/osteonectin, cwcv and kazal-like domain proteoglycan 1 (SPOCK1) axes was validated through RNA pull-down and dual-luciferase reporter assays. Our findings revealed that circ_PPAPDC1A was significantly upregulated in NSCLC with BM (P=0.018). Moreover, exosomes of circ_PPAPDC1A exhibited high diagnostic accuracy for BM, with an area under the curve of 0.83 (P = 0.003), and were closely associated with shorter progression-free survival (6.15 vs. 9.25 months; P = 0.019) and BM-free survival (5.41 vs. 7.75 months; P = 0.18). Functionally, circ_PPAPDC1A overexpression was associated with enhanced in vitro features related to BM, whereas silencing circ_PPAPDC1A showed opposite trends (P < 0.05). Mechanistically, circ_PPAPDC1A functions as efficient microRNA (miR-30a-3p) sponges, thereby activating its downstream functional target, SPOCK1 (P < 0.05). For the first time, we identified that circ_PPAPDC1A is significantly upregulated and associated with oncogenic effects in NSCLC with BM, potentially via sponging the miR-30a-3p-SPOCK1 pathway. circ_PPAPDC1A shows potential as a diagnostic biomarker and therapeutic target candidate for patients with NSCLC with BM, pending further validation.