FAL1 facilitates cisplatin resistance of lung adenocarcinoma via BMI1/BIM-mediated apoptosis–autophagy interaction

ZUP1 contributes to cisplatin resistance and treg-related signaling in non–small cell lung cancer

Acquired cisplatin resistance limits platinum chemotherapy efficacy in non–small cell lung cancer (NSCLC) and is accompanied by tumor immune microenvironment (TME) remodeling. We integrated public NSCLC single-cell RNA-seq datasets to compare cellular composition and CellChat-inferred communication between post-chemotherapy remission and relapse/resistant tumors, and validated ZUP1 expression and prognostic relevance in TCGA and external cohorts. In cisplatin-resistant A549/R and SK-MES-1/R cells, we generated stable ZUP1 knockdown and assessed proliferation, tumorsphere growth and formation, apoptosis (Annexin V/PI) and BAX/BCL2 expression, and xenograft growth. Tumor cell–peripheral Treg co-cultures were used to quantify the proportion of FOXP3⁺ cells within the gated CD4⁺ population. Natural-product screening was guided by molecular docking, and ZUP1–compound binding was evaluated by surface plasmon resonance (SPR). Peimisine responses were compared between parental and cisplatin-resistant cells. In A549/R cells, experimentally measured viability across a peimisine–cisplatin concentration matrix and cisplatin dose–response curves at fixed peimisine concentrations were used to evaluate changes in cisplatin sensitivity. Resistant tumors exhibited remodeled cellular composition and enhanced intercellular communication, including increased epithelial-to-Treg signaling. ZUP1 was upregulated in resistant models and associated with unfavorable prognosis. ZUP1 knockdown suppressed growth and tumorsphere formation, increased apoptosis, reduced tumorigenicity in vivo, and reduced the proportion of CD4⁺FOXP3⁺ Treg-like cells in co-culture. Peimisine directly bound ZUP1 by SPR, inhibited resistant cell growth, and was associated with lower estimated cisplatin IC₅₀ values in A549/R cells at fixed peimisine concentrations. ZUP1 contributes to the maintenance of cisplatin-resistant growth and is associated with enhanced Treg-related immunosuppressive signaling in NSCLC. Peimisine directly binds ZUP1 and may serve as a preliminary natural-product lead for further target-validation and combination studies.

FOXD1 upregulates DARS2-mediated glycolysis to drive cisplatin resistance in bladder cancer.

BACKGROUND Chemotherapy remains the most effective systemic treatment for bladder cancer (BLCA), with cisplatin as the primary agent. However, the frequent development of cisplatin resistance limits its clinical efficacy. Forkhead box D1 (FOXD1) is implicated in BLCA progression, yet its role in mediating cisplatin resistance remains unexplored. METHODS FOXD1 expression and its correlation with patient prognosis in BLCA were analyzed using the TCGA database. Cisplatin-resistant BLCA cell lines (T24-R and HT-1376-R) were established by treatment with gradient concentrations of cisplatin. qRT-PCR and Western blot were performed to detect the expression levels of FOXD1, β-catenin, and Aspartyl-tRNA Synthetase 2 (DARS2). Cell viability, proliferation, cell cycle, and apoptosis were assessed using CCK-8, colony formation assays, and flow cytometry. Co-IP was performed to examine the interaction between FOXD1 and β-catenin. Glycolysis levels in BLCA cells were determined using specific assay kits. RESULTS FOXD1 was highly expressed in BLCA tissues and correlated with poor prognosis. Knockdown of FOXD1 inhibited proliferation and cell cycle progression, promoted apoptosis, and enhanced cisplatin sensitivity in T24-R cells, while reducing β-catenin nuclear translocation and DARS2 expression. Overexpression of FOXD1 exerted the opposite effects on HT-1376-R cells and increased DARS2 expression, which were reversed by β-catenin knockdown. Moreover, knockdown of TCFs/LEF suppressed DARS2 expression. DARS2 was enriched in the glycolysis pathway. Its overexpression promoted glycolysis, proliferation, and cell cycle progression, while inhibiting apoptosis and cisplatin sensitivity in HT-1376-R cells-effects were reversed by 2-DG. CONCLUSION FOXD1 facilitates β-catenin nuclear translocation and upregulates DARS2 to enhance glycolysis, thereby promoting cisplatin resistance in BLCA. These findings identify the FOXD1/β-catenin/DARS2 axis as a potential therapeutic target for overcoming cisplatin resistance in BLCA clinically.

IDO1 Silencing Enhances Cisplatin Sensitivity in Gastric Cancer Cells via Modulation of Apoptosis and Oxidative Stress

Gastric cancer remains a leading cause of cancer-related mortality worldwide, largely due to resistance to platinum-based chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) has been implicated in tumor progression and immune evasion; however, its cell-intrinsic role in chemoresistance remains incompletely understood. This study demonstrates that IDO1 functions as a critical regulator of cisplatin sensitivity in gastric cancer cells through a ROS-mediated mechanism. IDO1 expression was suppressed using siRNA in two gastric cancer cell lines, AGS and MKN45, followed by cisplatin treatment. Cell viability, oxidative stress levels, apoptosis-related gene expression, and caspase-3/7 activity were assessed to evaluate the functional consequences of IDO1 knockdown. IDO1 silencing significantly enhanced cisplatin-induced cytotoxicity in both cell lines, accompanied by increased intracellular reactive oxygen species (ROS) levels and a marked transcriptional shift toward a pro-apoptotic gene expression profile characterized by upregulation of Bax and p53 and downregulation of anti-apoptotic Bcl-2. Critically, functional apoptosis analysis revealed that combined IDO1 silencing and cisplatin treatment markedly increased caspase-3/7 activity, confirming activation of the execution phase of apoptosis. These findings establish that IDO1 limits apoptotic susceptibility in a cell-intrinsic manner and contributes to cisplatin sensitivity in gastric cancer cells. The mechanistic basis involves IDO1’s ROS-scavenging function: by suppressing IDO1, cells lose their capacity to neutralize ROS, leading to excessive ROS accumulation that triggers mitochondrial dysfunction and activates p53-dependent apoptotic pathways. In conclusion, this study identifies IDO1 as a key regulator of oxidative stress-associated, caspase-dependent apoptosis in gastric cancer and suggests that targeting IDO1 in combination with platinum-based chemotherapy represents a promising strategy to enhance the efficacy of gastric cancer treatment. These findings provide a rationale for clinical translation and provide a foundation for future preclinical and clinical studies.

The MAZ-POLD1 Signaling Axis Drives Cisplatin Resistance in Bladder Cancer by Activating DNA Damage Repair

Simple Summary Cisplatin resistance severely limits therapeutic benefits for bladder cancer patients. In this study, we first verified that POLD1 was markedly overexpressed in cisplatin-resistant BC tissues and cells. Functional assays demonstrated that POLD1 knockdown remarkably impaired DDR capacity in cisplatin-resistant BC cells and restored their chemosensitivity to cisplatin in vitro, indicating that POLD1 is a key driver of cisplatin resistance. Further mechanistic experiments revealed that POLD1 physically interacted with ATM to facilitate ATM phosphorylation, which further triggered HR repair signaling. In addition, the transcription factor MAZ directly bound to the promoter region of POLD1 to transcriptionally activate POLD1 expression. Together, the MAZ–POLD1 axis represents a key driver of cisplatin resistance in bladder cancer. Our findings suggest that targeting this pathway may offer a promising new strategy to overcome drug resistance and improve clinical outcomes for bladder cancer patients.

Birinapant enhances cisplatin sensitivity in epithelial ovarian cancer through modulation of apoptotic and survival signaling pathways

SLC7A11 suppresses paclitaxel resistance and improves survival via the KLF2 regulatory axis associated with autophagy in ovarian cancer

SLC7A11 is well-established as a key mediator of ferroptosis. However, its functional role in regulating autophagy, particularly in the context of ovarian cancer (OC) chemoresistance, remains poorly characterized. Our preliminary results suggested that low SLC7A11 expression is associated with paclitaxel resistance in OC, likely through inhibition of autophagy. Despite this initial observation, systematic functional investigations into the role of SLC7A11 in autophagy regulation and OC chemoresistance are lacking, and the underlying molecular mechanisms remain unclear. Therefore, this study aims to elucidate how SLC7A11 mediates chemoresistance in OC through the regulation of autophagy. The effects of SLC7A11 modulation were assessed in paclitaxel-resistant and parental OC cells using functional assays. Autophagy was evaluated via transmission electron microscopy, immunofluorescence, and Western blotting. Autophagy was inhibited using 3-methyladenine or LC3B knockdown. A subcutaneous xenograft model was used for in vivo validation. Clinical relevance was analyzed using patient tissues. Proteomics, bioinformatics, molecular, and CCK-8 assays were integrated to investigate the SLC7A11/KLF2-autophagy axis. SLC7A11 knockdown enhanced the viability of paclitaxel-resistant OC cells (HeyA8-R) following paclitaxel treatment. In contrast, SLC7A11 overexpression sensitized both HeyA8-R cells and their parental HeyA8 cells to paclitaxel, as evidenced by reduced viability, increased intracellular paclitaxel accumulation, and elevated DNA damage. Moreover, SLC7A11 overexpression augmented autophagy-associated activity, and inhibition of autophagy partially attenuated SLC7A11-mediated sensitization to paclitaxel. In vivo studies showed that SLC7A11 suppressed tumor growth and overcame paclitaxel resistance in OC, accompanied by upregulated autophagy-related markers (LC3B, LC3B-II/I, and LAMP1). Mechanistically, SLC7A11 negatively regulated KLF2, a key oncogenic autophagy regulator, and the SLC7A11/KLF2 regulatory axis was associated with LC3B expression and autophagy-associated activity, which may contribute to paclitaxel sensitivity in OC. Clinically, low SLC7A11 expression correlated with chemoresistance and shorter survival in OC. Our findings underscore the significance of the SLC7A11/KLF2-autophagy regulatory axis in OC paclitaxel resistance. They also suggest that SLC7A11 may serve as a prognostic biomarker and therapeutic target for overcoming OC chemoresistance.