Background Current liver cancer research lacks reliable in vitro models that replicate tumor pathophysiology. This study establishes primary liver cancer (PLC) organoids from three major subtypes-hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular-cholangiocarcinoma (CHC)-to enable precise diagnostics and personalized therapies through comprehensive genomic profiling. Methods Organoid cultures were generated from 11 PLC patients (5 HCC, 3 ICC, 3 CHC). Whole exome sequencing (WES), RNA-seq, and single-cell RNA-seq (scRNA-seq) were performed to analyze molecular differences. Drug screening targeting subtype-specific pathways was conducted to validate sequencing findings. Results WES and RNA-seq confirmed that organoids retained parental tumor genetics and heterogeneity, distinct from paracancerous tissues. scRNA-seq revealed distinct cell populations in HCC, ICC, and CHC organoids. Lipid metabolism was enriched in HCC organoids; tumor migration pathways were upregulated in ICC organoids; and mitochondrial function was enhanced in CHC organoids. Rosuvastatin inhibited HCC growth by targeting lipid metabolism, while pemigatinib reduced ICC malignancy by suppressing epithelial-mesenchymal transition. Regorafenib impaired mitochondrial function in CHC organoids, slowing progression. Conclusions PLC-derived organoids serve as robust tools for biomarker discovery and drug screening. scRNA-seq elucidates inter-and intra-tumoral heterogeneity, offering insights for precision therapy in liver cancer. This model advances personalized treatment strategies for diverse PLC subtypes.

Ovarian cancer patients requiring intensive care unit (ICU) admission face particularly grave prognosis, yet current prognostic models rely on static baseline characteristics and generic severity scores, neglecting the rich temporal dynamics of vital signs that may better capture physiological deterioration patterns. To develop and validate an interpretable Long Short-Term Memory (LSTM) neural network integrating hourly vital signs and static features for predicting 28-day mortality in ICU-admitted ovarian cancer patients. This retrospective multicenter study utilized MIMIC-IV (2008–2022) and SICdb (2013–2021) databases. Adult ovarian cancer patients with first ICU admission, length of stay ≥ 24 h, and complete hourly measurements of six vital signs (blood pressures, heart rate, respiratory rate, oxygen saturation) were included. MIMIC-IV was split into training (n = 269) and internal validation (n = 115) sets, while SICdb (n = 154) served as external validation. A dual-pathway LSTM network integrated temporal and static features (age, BMI, SOFA score). Model performance was assessed using AUROC, calibration metrics, and compared against traditional ICU scores and five static-only machine learning baselines. Five-fold cross-validation and 100 repeated temporal ablation trials assessed robustness. SHapley Additive exPlanations (SHAP) analysis quantified feature importance and temporal dynamics. The LSTM model achieved AUROC of 0.845 (95

Sepsis-associated acute kidney injury (SA-AKI) is a significant clinical challenge due to its prevalence in intensive care units. This study evaluated the diagnostic utility of serum miR-151a-3p for SA-AKI, aiming to provide new insights into early diagnosis and mechanistic research. Serum miR-151a-3p levels were determined via qRT-PCR and assessed for clinical correlations (Pearson correlation), risk association with SA-AKI (logistic regression), and diagnostic efficacy (ROC curve analysis). In vitro, the injury model was constructed by inducing TCMK-1 cells with LPS, and the miR-151a-3p mimic was transfected to observe its effects on inflammatory and oxidative stress. Finally, a binding relationship between miR-151a-3p and AKT3 was validated by employing both bioinformatics and dual-luciferase assay. In SA-AKI patients, miR-151a-3p was significantly decreased, and its expression level showed a significant negative correlation with disease severity and representative indicators of renal function. MiR-151a-3p is an independent protective factor for SA-AKI, with an AUC of 0.883 for predicting SA-AKI. In vitro experiments confirmed that overexpression of miR-151a-3p significantly alleviated LPS-induced inflammatory responses and oxidative stress damage. The dual-luciferase assay confirmed the binding relationship between AKT3 and miR-151a-3p. MiR-151a-3p is closely related to the severity of SA-AKI. It can be used as a potential biomarker for the early prediction of the occurrence of SA-AKI. Overexpression of miR-151a-3p alleviates LPS-induced renal tubular epithelial cell injury.

Colorectal cancer (CRC) progression is driven by diverse molecular mechanisms, underscoring the urgent need for novel therapeutic strategies, especially for liver metastases. Through an integrated analysis of multiple single-cell RNA sequencing databases, zinc finger protein-like 1 (ZFPL1) is identified as a gene specifically enriched in malignant cells from both primary and metastatic CRC. Multi-omics investigations demonstrate that high ZFPL1 expression correlates with aggressive clinicopathological features and poor survival. Functionally, ZFPL1 promotes tumor proliferation, invasion, and migration both in vivo and in vitro. Mechanistically, ZFPL1 directly binds argininosuccinate synthase 1 (ASS1), shielding its K57 residue from tripartite motif containing 33-mediated ubiquitination to prevent proteasomal degradation. This stabilization activates urea cycle metabolism, driving CRC progression. Crucially, ZFPL1 deficiency remodels the tumor microenvironment by reducing immunosuppressive populations-M2 macrophages, and promoting pro-inflammatory M1 polarization. Virtual screening identifies Salvianolic acid B (Sal B) as a ZFPL1 inhibitor, which disrupts ZFPL1-ASS1 binding, triggering ASS1 ubiquitination and degradation. In vivo, Sal B synergized with anti-PD-1 therapy, significantly reducing tumor burden versus monotherapy. These findings establish ZFPL1 as a key regulator of CRC progression through ASS1-dependent urea cycle activation and immunomodulation, nominating the ZFPL1-ASS1 axis as a therapeutic target, with Sal B demonstrating combinatorial potential with immunotherapy.

Chemoresistance remains the major barrier to cancer treatment. Metabolic and epigenetic reprogramming are involved in this process; however, the precise roles and mechanisms are largely unknown. Here, we report that lactate-induced lactylation promotes chemoresistance to anthracyclines by regulating homologous recombination (HR) repair. Using the global lactylome, we revealed the landscape of differentially lactylated sites and proteins in cancer cells isolated from resistant and nonresistant tumors. Specifically, BLM, a crucial helicase in the HR repair process, is highly lactylated at Lys24 by AARS1 in response to chemotherapy. Mechanistically, hyperlactylation of BLM improves its stability by inhibiting MIB1-mediated ubiquitination and increasing its interaction with DNA repair factors, promoting DNA end resection and HR repair. Delactylation of BLM via the Lys24 mutation impairs HR repair and increases anthracycline chemosensitivity. Irinotecan shows synergistic effects and safety for alleviating anthracycline resistance by targeting BLM lactylation and suppressing HR repair in pancancer PDX models. A single-arm, phase I study (identifier NCT06766266) initiated by us suggested that the combination of irinotecan liposomes plus EPI is a feasible and safe treatment strategy for patients with anthracycline-resistant bladder cancer who experience recurrence. These findings exemplify how glycolytic reprogramming regulates HR repair through promoting protein lactylation and highlight the promising therapeutic potential of irinotecan for reversing anthracycline chemoresistance by suppressing BLM lactylation.

This review comprehensively examines the biological and molecular mechanisms underlying wound healing, focusing on inflammation, signaling pathways, and microenvironmental imbalances. By comparing traditional and emerging therapies, we highlight innovative approaches such as gene editing, stem cell therapy, and nanotechnology, which offer new perspectives for enhancing wound treatment outcomes. This study underscores the integration of modern medicine with traditional practices, providing a robust theoretical foundation for future clinical applications.

Radiotherapy is the cornerstone of treatment for cervical cancer, yet the variability of patient response demands a deeper understanding of the molecular determinants of radioresistance. In this study, we investigated the molecular and cellular mechanisms of radioresistance in cervical cancer through a comprehensive multi-omics and machine learning approach. We downloaded and processed transcriptome sequencing, methylation and single-cell sequencing data from the TCGA and GEO databases. Differential gene and methylation analyses were performed to identify radioresistance-related markers. Single-cell data were processed using Seurat and annotated using CellTypist. Prognostic models were constructed and validated through downscaling, cell scoring, trajectory analysis and machine learning. Additionally, immune infiltration and drug sensitivity analyses were conducted. The differential analysis identified 845 up-regulated and 460 down-regulated genes associated with radioresistance. The methylation analysis identified 3042 down-regulated and 158 up-regulated gene loci. Single-cell sequencing revealed 43,475 cells and 13 cell types, with aneuploid cells predominantly present in epithelial cells. Cell scoring highlighted dispersed immune cells, with monocytes, ILCs, and T cells being the most relevant to radiotherapy resistance. The machine learning approach constructed a robust prognostic model using Cox regression and validated it on multiple datasets. The prognostic model demonstrated good predictive ability in assessing radiotherapy efficacy and immune infiltration. Drug screening identified several potential therapeutic candidates with high sensitivity for high-risk patients. This study provides a comprehensive multi-omics analysis and machine learning framework for identifying and validating molecular markers and prognostic models associated with radioresistance in cervical cancer, providing insights for personalized treatment strategies.

Fetal growth restriction (FGR) severely affects the health outcome of newborns and represents a major cause of perinatal morbidity. The precise involvement of circCULT1 in the progression of FGR remains unclear. We performed next-generation sequencing and RT-qPCR to identify differentially expressed circRNAs in placental tissues affected by FGR by comparing them with unaffected counterparts. Edu, flow cytometry, and transwell assay were conducted to detect HTR8/SVneo cell's function in regard to cell proliferation, migration, and invasion. The interaction between circCUL1 and hsa-miR-30e-3p was assessed through dual-luciferase reporter assays, validation of the interaction between circCUL1 and ANXA1 was performed using RNA pulldown and immunoprecipitation assays. Western blot analysis was performed to evaluate protein levels of autophagy markers and components of the PI3K/AKT signaling pathway. A knockout (KO) mouse model was established for homologous mmu-circ-0001469 to assess fetal mouse growth and development indicators. Our findings revealed an upregulation of circCUL1 expression in placental tissues from patients with FGR. We found that suppression of circCUL1 increased the trophoblast cell proliferation, migration, and invasion, circCUL1 could interact with hsa-miR-30e-3p. Further, circCUL1 stimulated autophagy, modulating trophoblast cell autophagy via the ANXA1/PI3K/AKT pathway, and a notable disparity was observed, with KO mice displaying accelerated embryo development and exhibiting heavier placentas in comparison to wild-type C57BL/6 mice. By modulating the ANXA1/PI3K/AKT signaling pathway through the interaction with hsa-miR-30e-3p, circCUL1 promotes autophagy while concurrently suppressing trophoblast cell proliferation, migration, and invasion. These findings offer novel insights into potential diagnostic markers and therapeutic targets for FGR research.

For adoptive therapy with T cell receptor engineered T (TCR-T) cells, the quantity and quality of the final cell product directly affect their anti-tumor efficacy. The post-transfer efficacy window of TCR-T cells is keen to optimizing attempts during the manufacturing process. Cbl-b is a E3 ubiquitin ligase previously shown with critical negative impact in T cell functions. This study investigated whether strategic inclusion of a commercially available small inhibitor targeting Cbl-b (Cbl-b-IN-1) prior to T cell activation could enhance the quality of the final TCR-T cell product. Examination with both PBMCs and TCR-T cells revealed that Cbl-b-IN-1 treatment promoted TCR expression efficiency, T cell proliferation potential and, specifically, cell survival capability post antigenic stimulation. Cbl-b-IN-1 exposure facilitated T cells in maintaining less differentiated states with enhanced cytokine production. Further, we found that Cbl-b-IN-1 effectively augmented the activation of TCR signaling, shown by increased phosphorylation levels of Zeta-chain-associated protein kinase 70 (ZAP70) and phospholipase c-γ1 (PLCγ1). In conclusion, our results evidence that the inclusion of Cbl-b inhibitor immediately prior to TCR-T cell activation may enhance their proliferation, survival, and function potentials, presenting an applicable optimization strategy for immunotherapy with adoptive cell transfer.

Breast cancer is the most common malignant tumor in women and the leading cause of cancer death in women. About 30% of breast cancer patients have metastasis every year, which greatly increases the mortality rate of breast cancer. The main target organs for metastasis are bone, brain, liver and lung. The breast cancer liver metastasis (BCLM) mechanism is not fully clarified. This is a complex process involving multiple factors, which is not only related to the microenvironment of the primary tumor and liver, but also regulated by a variety of signaling pathways. Clarifying these mechanisms is of great help to guide clinical treatment. With the in-depth study of BCLM, a variety of new treatment schemes such as targeted therapy and endocrine therapy provide new ideas for the cure of BCLM. In this review, we will summarize the molecular mechanism and treatment of BCLM.

This study is aimed at exploring the potential mechanism of angiogenesis, a biological process-related gene in breast cancer (BRCA), and constructing a risk model related to the prognosis of BRCA patients. We used multiple bioinformatics databases and multiple bioinformatics analysis methods to complete our exploration in this research. First, we use the RNA-seq transcriptome data in the TCGA database to conduct a preliminary screening of angiogenesis-related genes through univariate Cox curve analysis and then use LASSO regression curve analysis for secondary screening. We successfully established a risk model consisting of seven angiogenesis-related genes in BRCA. The results of ROC curve analysis show that the risk model has good prediction accuracy. We can successfully divide BRCA patients into the high-risk and low-risk groups with significant prognostic differences based on this risk model. In addition, we used angiogenesis-related genes to perform cluster analysis in BRCA patients and successfully divided BRCA patients into three clusters with significant prognostic differences, namely, cluster 1, cluster 2, and cluster 3. Subsequently, we combined the clinical-pathological data for correlation analysis, and there is a significant correlation between the risk model and the patient's T and stage. Multivariate Cox regression curve analysis showed that the age of BRCA patients and the risk score of the risk model could be used as independent risk factors in the progression of BRCA. In particular, based on this angiogenesis-related risk model, we have drawn a matching nomogram that can predict the 5-, 7-, and 10-year overall survival rates of BRCA patients. Subsequently, we performed a series of pan-cancer analyses of CNV, SNV, OS, methylation, and immune infiltration for this risk model gene and used GDSC data to explore drug sensitivity. Subsequently, to gain insight into the protein expression of these risk model genes in BRCA, we used the immunohistochemical data in the THPA database for verification. The results showed that the protein expressions of IL18, RUNX1, SCG2, and THY1 molecules in BRCA tissues were significantly higher than those in normal breast tissues, while the protein expressions of PF4 and TNFSF12 molecules in BRCA tissues were significantly lower than those in normal breast tissues. Finally, we conducted multiple GSEA analyses to explore the biological pathways these risk model genes can cross in cancer progression. In summary, we believe that this study can provide valuable data and clues for future studies on angiogenesis in BRCA.

Abstract Background Fetal growth restriction seriously affects the health of newborns. However, the cause of FGR is unclear. Circular RNAs (CircRNAs) are a novel type of endogenous noncoding RNAs that regulate target gene expression by interacting with microRNA (miRNA) .The present research was major in investigating the regulation association among circCUL1, miR-30e, ATG7/14 and MAPK1 in FGR, and we explored the mechanism underlying pathogenesis of FGR Results circCUL1 promotes autophagy in placental trophoblast cells. Mechanism studies have found that circCUL1 regulates trophoblast autophagy through the miR-30e-ATG7/14 and ANXA1/PI3K/AKT pathways. We also observed that knocking out circCUL1 promoted mouse development. Conclusions our research suggested that circCUL1 may be involved in the pathogenesis of FGR. circCUL1 may be a potential diagnostic marker and therapeutic target of FGR.

CDCA3 is an essential regulator in cell mitosis and can regulate many physiological and pathological processes in the human body by stimulating certain proteins such as cell cycle regulatory proteins, transcription factors, and signal transduction molecules. Although several studies have shown that dysregulation of CDCA3 is a common phenomenon in human cancers, no systematic pan-cancer analysis has been performed. In this study, we comprehensively investigated the role of CDCA3 in 33 human cancer types by utilizing multiple cancer-related databases and bioinformatics analysis tools, including TCGA, GTEx, GEPIA, TIMER, STRING, Metascape, and Cytoscape. Evidence from bioinformatics databases shows that CDCA3 is overexpressed in almost all human cancer types, and its overexpression is significantly associated with survival in patients with more than ten cancer types. CDCA3 expression positively correlates with immune cell infiltration levels in multiple human cancer types. Furthermore, the results of the GSEA analysis revealed that overexpression of CDCA3 may promote the malignant progression of cancer by activating various oncogenic signaling pathways in human cancers. In conclusion, our pan-cancer analysis provides a comprehensive overview of the oncogenic role of CDCA3 in multiple human cancer types, suggesting that CDCA3 may serve as a potential therapeutic target and prognostic biomarker in multiple human cancer types.

This research aims to investigate the effect of lncRNA KB-1980E6.3 on the biological behaviour of breast cancer cells under normoxic conditions and the underlying molecular mechanism. The expression of KB-1980E6.3 in breast cancer tissues and cells was detected by RT-qPCR. The proliferation, migration and invasion of cells were evaluated by CCK-8, colony formation, scratch and Transwell assays; KB-1980E6.3-related xenograft models were established for in vivo studies. The protein expression of PI3K, p-PI3K, AKT and p-AKT was validated by western blotting analysis. The levels of KB-1980E6.3 are significantly upregulated in breast cancer tissues and cells and are related to the poor prognosis. Functional research both in vivo and in vitro revealed that the downregulation of KB-1980E6.3 expression significantly decreased cell proliferation, invasion and migration, while ectopic KB-1980E6.3 expression obviously promoted these biological phenotypes. In terms of the mechanism, KB-1980E6.3 is involved in the activation of the PI3K/AKT signalling pathway. Knockdown of KB-1980E6.3 reduced the expression of the p-PI3K and p-AKT proteins, whereas KB-1980E6.3 overexpression showed the opposite result. The agonist 740Y-P and inhibitor LY294002 reversed the effect of KB-1980E6.3 knockdown and overexpression on the PI3K/AKT pathway in BC cells. KB-1980E6.3 promotes the proliferation, invasion and migration of breast cancer cells by activating PI3K/AKT signalling, which can be used as a potential target for breast cancer therapy.

Breast cancer (BC) is the second leading cause of death among women and is highly heterogeneous. Three pyroptosis (PR) subtypes were identified in patients with BC from the Cancer Genome Atlas Database (TCGA) cohorts using 20 PR-related regulators, which illustrate a strong association between BC prognosis and PR. Lung metastasis commonly occurs in the advanced stages of BC, resulting in a poor quality of life. Eight differentially expressed (DE) lncRNAs were identified using LASSO-Cox analysis between PR-related and BC lung metastasis. Moreover, a BRCA risk-score (RS) model was established using multivariate Cox regression, which correlated with prognosis in TCGA-BRCA. Clinical characteristics, tumor mutation burden, and tumor immune cell infiltration were extensively investigated between high- and low-RS groups. Similarly, a lower RS implied longer overall survival, greater inflammatory cell infiltration, and better immunotherapeutic response to PD-1 blockers. Our findings provide a foundation for future studies targeting PR and confirme that RS could predict the prognosis of patients with BC.

Background: Hepatocellular carcinoma (HCC) is the world’s most common cause of cancer death. Therefore, more molecular mechanisms need to be clarified to meet the urgent need to develop new detection and treatment strategies. Methods: We used TCGAportal, Kaplan–Meier Plotter, the Cistrome DB Toolkit Database, MExpress, GEPIA2, and other databases to discuss the expression profiles, possible biological function, and potential prognostic value of versican (VCAN) in HCC. We conducted cell experiments such as Transwell migration and invasion assays, wound healing assay, and CCK8 experiment to explore the function of VCAN in HCC. Result: We selected three HCC transcriptome databases GSE124535, GSE136247, and GSE144269 and analyzed the overexpressed genes contained in them. The overlapping genes were found by the Venn map, and two interacting network modules were found by Mcode. Module 1 was mainly related to mitosis and cell cycle, and module 2 was mainly related to EMT, angiogenesis, glycolysis, and so on. We found that the seed gene in module 2 is VCAN. Data from TCGAportal showed that compared with normal tissues, the expression of VCAN was up-regulated in HCC tissues. The patients with high expression of VCAN had shorter distant recurrence-free survival and overall survival. Multiple possible VCAN interactions had also been identified. These results revealed that the level of VCAN was higher in the subtypes of HCC with higher malignant degree and was connected to the poor prognosis. In addition, the treatment of VCAN with DNA methyltransferase inhibitors and transcription factor inhibitors may improve the prognosis of patients with HCC. Conclusion: Our findings systematically elucidated the expression profile and different prognostic values of VCAN in HCC, which may provide new therapeutic targets and potential prognostic biomarkers for HCC patients.

Abstract Purpose To improve the accuracy of the preoperative diagnosis of ovarian cystadenofibroma (CAF) or adenofibroma (AF). Methods Clinical symptoms, laboratory results, imaging features, and pathological results of 11 patients with 11 histologically proven ovarian CAF/AF were reviewed retrospectively. The computed tomography (CT) and magnetic resonance imaging (MRI) features of the tumor including location, number, size, internal characteristics, CT density or MRI signal intensity, enhancement performance, lymphadenopathy, and amount of ascites were comprehensively evaluated. Results With regard to the clinical findings, results of serum cancer antigen 125 (CA125), cancer antigen 199 (CA199), and other laboratory tests were normal in most cases (81.8%, 9/11). The imaging features of the 11 lesions were as follows: unilateral occurrence, well-defined boundary, round or roundish, unilocular (63.6%, 7/11), cystic mass (81.8%, 9/11), multilocular (27.3%, 3/11), black sponge sign (18.2%, 2/11), carpet sign (81.8%, 9/11), residual ovary sign (45.5%, 5/11), papillary nodule clusters (45.5%, 5/11), and small vesicle with an acute angle to the inner cyst wall (18.2%, 2/11). The signal intensity of the solid component was isointense or hypointense on T2-weighted imaging and hypo intense on diffusion-weighted imaging. The CT value of the lesions ranged from 21 Hounsfield units (Hu) to 45 Hu. A slight to moderate enhancement degree occurred in more than half of the lesions (54.5%, 6/11). No or a small amount of ascites was present in these cases. Histologic examination revealed SCAF (45.5%, 5/11), SAF (27.3%, 3/11), and borderline CAF/AF (27.3%, 3/11). No necrosis, hemorrhage, or calcification was observed in any of these masses. Conclusion Ovarian CAF/AF usually mimics malignancy, demonstrating a cystic mass combined with solid component on CT or MR images. The integrity of case data including laboratory results and imaging features can help radiologists make an accurate preoperative diagnosis. No or a small amount of ascites may narrow the differential diagnosis.

Hepatocellular carcinoma(HCC) is the world's most common cause of cancer death. Therefore, more molecular mechanisms need to be clarified to meet the urgent need to develop new detection and treatment strategies. We selected three liver cancer transcriptome database GSE124535, GSE136247, GSE144269, and analyze the overexpressed genes contained in them. The overlapping genes were found by Venn map, and two interacting networks module, were found by Mcode. Module1 is mainly related to mitosis and cell cycle, and module2 is mainly related to EMT, angiogenesis, glycolysis and so on. We found that the seed gene in module2 is VCAN. The purpose of this study is to study the expression characteristics of VCAN gene in HCC, and to explore its role in the occurrence and development of HCC and its possible mechanism. Data from TCGAportal shows that compared with normal tissues, the expression of VCAN is up-regulated in HCC tissues. The patients with high expression of VCAN had shorter distant recurrence-free survival and overall survival. The effects of VCAN expression on cell proliferation, invasion and migration were evaluated in vitro by using gene knockout and overexpression strategies. Multiple possible VCAN interactions have also been identified. These result reveal that the level of VCAN is higher in the subtypes of HCC with higher malignant degree and is connected to the poor prognosis. In addition, the treatment of VCAN with DNA methyltransferase inhibitors and transcription factor inhibitors may improve prognosis of patients with liver cancer.

Tamoxifen (TAM) resistance constitutes a challenge in managing estrogen receptor (ER)α+ breast cancer patients. G-protein-coupled estrogen receptor (GPR30/GPER), which reportedly initiates TAM resistance in ERα+/ GPR30+ breast cancers, is detected in the breast cancer microenvironment, especially cancer associated fibroblasts (CAFs). Herein, considering that GPR30 mediates transcriptional regulation in different cell backgrounds, a microarray strategy was applied in immortalized CAFs derived from primary breast cancer samples, resulting in the identification of 165 GPR30 target genes, among which HMGB1 was confirmed to be upregulated by 17-β estradiol(E2)- and TAM-triggered GPR30 activation in CAFs. Activated GPR30 increased extracellular HMGB1 secretion by CAFs, which was reduced by blocking PI3K/AKT signaling using G15 or LY294002. GPR30-induced HMGB1 upregulation triggered MEK/ERK signaling, leading to increased autophagic behavior to protect cancer cells from TAM-induced apoptosis, mimicking the recombinant HMGB1-mediated increase in cancer cell resistance potential to TAM. MEK/ERK signaling blockage by U0126 decreased the autophagic behavior and resistance ability of cancer cells to TAM. CAF-expressed GPR30 induced TAM resistance via HMGB1 in vivo. Overall, TAM upregulated HMGB1 expression and secretion in CAFs via GPR30/PI3K/AKT signaling, and the secreted HMGB1 induced autophagy to enhance TAM resistance in MCF-7 cells in an ERK-dependent manner. Thus, targeting GPR30 and downstream cascades may be an effective strategy to attenuate the resistance of ERα-positive breast tumors to endocrine therapy.