bims-meract 2026-09-27 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–09–27
twenty-one papers selected by
Andrea Morandi, Università degli Studi di Firenze

ZDHHC9 regulates lipid metabolic reprogramming by mediating palmitoylation of ACSL3 to promote Cetuximab resistance in Colorectal Cancer.
Metabolic reprogramming underlying EGFR-TKI resistance in lung cancer.
Inducing oxidative stress by targeting the cholesterol biosynthesis pathway augments the efficacy of bortezomib in multiple myeloma.
SUCLG2 contributes to platinum resistance in lung adenocarcinoma through enhancing succinylation of GAC and glutamine metabolism.
Inhibition of EphA2 triggers ferroptosis by disrupting USP38mediated SLC7A11 stabilization in chemoresistant gastric cancer.
DDR1 sustains ferroptosis resistance in pancreatic ductal adenocarcinoma via SLC40A1-mediated iron homeostasis.
NRF2 signaling drives chemoresistance in NSCLC and glioblastoma.
The deubiquitinase USP5 mediates anti-PD-L1 resistance in breast cancer by stabilizing FOXM1 to upregulate Nectin2.
Nucleolin Alterations and ROS Production Associate With Sensitivity of AML Cells to Venetoclax.
IRE1α-XBP1s signaling links lipid homeostasis to hypoxic maladaptation and KRAS inhibitor responses in pancreatic ductal adenocarcinoma.
Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.
The AURKA-PTTG1 signaling axis induces enzalutamide resistance in prostate cancer.
Integrative multi-omics analysis identifies LIPA as a prognostic hub and ferroptosis regulator in lung adenocarcinoma.
The role and mechanism of CHST6-mediated lactation modification in lenvatinib resistance in hepatocellular carcinoma cells.
SPOP-mediated ZMYND8 ubiquitination and phase separation exclusion drives mTOR inhibitor resistance in kidney cancer.
Levofloxacin enhances 5-fluorouracil efficacy in colorectal cancer by activating the DDR-TP53-mitochondrial apoptosis axis.
Sphingolipids as central regulators of therapy resistance and immunity in lung cancer.
Obesity associated elevated leptin might contribute to paclitaxel resistance via PLCB1/IP3R1 axis in head and neck cancers.
Integrated genetic screening identifies FEN1 as a selective vulnerability and temozolomide resistance mediator in glioblastoma stem cells.
Sorafenib-loaded porphyrin-phospholipid liposomes for enhanced chemophototherapy in hepatocellular carcinoma.
BCLXL blockade rewires cell fate to overcome PARP inhibitor resistance in ovarian cancer.

Exp Cell Res. 2026 Sep 25. pii: S0014-4827(26)00296-X. [Epub ahead of print] 115179

ZDHHC9 regulates lipid metabolic reprogramming by mediating palmitoylation of ACSL3 to promote Cetuximab resistance in Colorectal Cancer.

Kun Song, Zuyin Ge, Yunxiao Lin, Zhaolan Xie, Tiangong Wang, Jingduo Hao.

  Tumor metastasis and drug resistance are the leading causes of mortality in patients with colorectal cancer (CRC). Protein palmitoylation exerts a pivotal role in the metabolic reprogramming across various malignancies. However, the precise mechanisms underlying its contribution to CRC metastasis and drug resistance via lipid metabolism reprogramming remain elusive. Therefore, this study aimed to elucidate the specific role of ZDHHC9 in conferring Cetuximab resistance in CRC. Initial phenotypic screening with the broad-spectrum inhibitor 2-BP implicated palmitoylation in Cetuximab resistance. Subsequently, targeted genetic experiments identified ZDHHC9 as the specific molecular driver. Furthermore, ZDHHC9 was significantly upregulated in CRC tissues and strongly correlated with poor patient prognosis. Subsequent in vitro and in vivo experiments demonstrated that ZDHHC9 functionally promoted Cetuximab resistance in CRC. Mechanistically, ZDHHC9 physically interacted with ACSL3 and enhanced its palmitoylation, thereby driving the malignant progression of CRC. Moreover, we identified cysteine 468 (C468) as the critical residue responsible for the palmitoylation of ACSL3. Notably, ectopic overexpression of ACSL3 effectively rescued the suppression of CRC cell proliferation induced by ZDHHC9 depletion. In conclusion, our findings establish the ZDHHC9-ACSL3 axis as a preclinically validated resistance driver and an actionable metabolic vulnerability for overcoming Cetuximab resistance in CRC.

Keywords:  ACSL3; Cetuximab resistance; Colorectal cancer; Metabolic reprogramming; Palmitoylation; ZDHHC9

DOI:  https://doi.org/10.1016/j.yexcr.2026.115179
Biochim Biophys Acta Mol Cell Res. 2026 Sep 21. pii: S0167-4889(26)00122-9. [Epub ahead of print]1873(8): 120223

Metabolic reprogramming underlying EGFR-TKI resistance in lung cancer.

Xiaolong Huang, Tao Cheng, Fengkai Xu, Di Ge, Cheng Zhan.

  Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the clinical efficacy in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, acquired resistance to EGFR-TKIs remains an unavoidable therapeutic bottleneck. The metabolic reprogramming underlying this resistance is crucial for understanding the resistance mechanisms and identifying new therapeutic targets. Recently, an increasing number of studies have focused on the impact of metabolic reprogramming on acquired EGFR-TKI resistance. Collectively, this review reveals the core driving role of metabolic reprogramming in EGFR-TKI resistance, focuses on the systematic adjustments of resistant cells in terms of glucose metabolism, lipid metabolism, amino acid metabolism, and nucleotide metabolism, and also pays attention to the effects of ferroptosis and changes in the metabolic pattern of the tumor immune microenvironment on EGFR-TKI resistance. In addition, we summarize the application of potential therapeutic approaches targeting metabolic reprogramming in overcoming lung cancer resistance.

Keywords:  EGFR-TKI resistance; Metabolic reprogramming; NSCLC

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120223
Free Radic Biol Med. 2026 Sep 21. pii: S0891-5849(26)01170-6. [Epub ahead of print]256 650-663

Inducing oxidative stress by targeting the cholesterol biosynthesis pathway augments the efficacy of bortezomib in multiple myeloma.

Chunfan Li, Fuqiang Wang, Hongwei Peng, Meng Chen, Yafang Pu, Xiang Lin, Shuai Wang, Fei Li, Zhimin Gu.

  Proteasome inhibitors, particularly bortezomib (BTZ) which induces oxidative stress, remain the cornerstone of multiple myeloma (MM) therapy. However, resistance driven by metabolic reprogramming and redox adaptation limits their long-term efficacy. Here, we identify a cholesterol biosynthesis-dependent antioxidant mechanism that shields MM cells from BTZ-induced generation of reactive oxygen species (ROS). High cholesterol biosynthesis activity characterizes BTZ-nonresponsive plasma cells and correlates with poor prognosis. Genetic silencing of SREBF2, the master transcriptional regulator of cholesterol metabolism, sensitized MM cells to BTZ both in vitro and in vivo. Pharmacological inhibition of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, with the clinically approved atorvastatin likewise enhanced the anti-myeloma activity of BTZ in vitro and in vivo. Mechanistically, the lipid raft protein FLOT1 promoted FOXO3 nuclear translocation and SREBF2 activation, thereby driving increased cholesterol biosynthesis and accumulation of the intermediate metabolite 7-dehydrocholesterol (7-DHC), a critical antioxidant that mitigated BTZ-induced cytotoxicity. Decreasing 7-DHC production by disrupting SREBF2 activation or treating with atorvastatin impaired the cellular ROS detoxification capacity and enhanced BTZ-induced cytotoxicity. Collectively, our findings identify that MM cells resist therapy-induced ROS by accumulating 7-DHC through activation of cholesterol biosynthesis, and provide preclinical evidence for repurposing statins to augment the efficacy of BTZ therapy.

Keywords:  7-Dehydrocholesterol; Bortezomib resistance; Cholesterol biosynthesis; Multiple myeloma; Oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.019
Apoptosis. 2026 Sep 23. pii: 231. [Epub ahead of print]31(10):

SUCLG2 contributes to platinum resistance in lung adenocarcinoma through enhancing succinylation of GAC and glutamine metabolism.

Zuorui Wang, Hui Wang, Lei Wang, Jiayuan Chen, Lei Jiang, Wenxin Deng, Jing Xu, Yaoguang Hua, Yifan Shi, Yi Yuan, Menglin Huang, Xiangpei Cui, Lanxi Bai, Defu Li, Bentong Yu, Qifan Hu.

  Platinum-based drugs constitute first-line chemotherapy for lung adenocarcinoma (LUAD), yet resistance emerges in 50-70% of patients, representing a major clinical challenge. Synthetase GDP-forming subunit β (SUCLG2), the beta subunit of succinyl-CoA synthetase, is a key enzyme in the tricarboxylic acid (TCA) cycle. Using untargeted proteomic profiling, we identified SUCLG2 as a potential contributor of platinum resistance in LUAD. Further knockout of SUCLG2 significantly enhanced cellular sensitivity to platinum-based drugs. Mechanistically, using targeted metabolomics, we found that SUCLG2 conferred platinum resistance by promoting glutamine metabolism and facilitating the succinylation of glutaminase (GAC). This post‑translational modification enhanced GAC activity, thereby reducing ROS generation and suppressing apoptosis in LUAD cells. SUCLG2 was found to be highly expressed in both LUAD tissues and platinum-resistant cell lines. Consistent with cellular findings, animal experiments confirmed that elevated SUCLG2 expression critically contributes to platinum resistance in vivo. Our findings provide new insights into the molecular mechanisms underlying platinum resistance in LUAD and suggest novel therapeutic strategies.

Keywords:  GAC; Glutamine metabolism; Lung adenocarcinoma; Platinum resistance; SUCLG2

DOI:  https://doi.org/10.1007/s10495-026-02443-7
Cell Mol Life Sci. 2026 Jul 30. pii: 341. [Epub ahead of print]83(1):

Inhibition of EphA2 triggers ferroptosis by disrupting USP38mediated SLC7A11 stabilization in chemoresistant gastric cancer.

Runsha Xiao, Yan Mo, Jin Zhou, Yi Xu, Kuo Kang, Zhikang Chen, Yuanyuan Jiang, Chengmin Li, Xueping Feng, Zihua Chen, Si Chen, Chen Lai.

  Aberrant expression of EphA2 (Ephrin receptor A2) in gastric cancer (GC) promotes chemoresistance by suppressing ferroptosis, yet the underlying mechanism remains poorly defined. In this study, we show that EphA2 confers resistance to platinum-based chemotherapy by suppressing ferroptosis through redox homeostasis regulation. Mechanistically, EphA2 directly phosphorylates and activates the deubiquitinase USP38, which in turn stabilizes SLC7A11 by preventing its proteasomal degradation. Elevated SLC7A11 sustains intracellular glutathione homeostasis, attenuates lipid peroxidation, and limits reactive oxygen species accumulation, thereby enabling GC cells to evade ferroptotic cell death under chemotherapeutic stress. Importantly, genetic or pharmacological disruption of the EphA2-USP38 interaction leads to SLC7A11 destabilization, excessive ROS accumulation, ferroptosis induction, and restoration of chemosensitivity. Together, these findings identify the EphA2-USP38/ROS axis as a key determinant of oxaliplatin resistance in GC and highlight a promising therapeutic target for overcoming chemotherapy resistance by reactivating ferroptosis.

Keywords:  Chemoresistance; Deubiquitinase; Metabolic reprogramming; Mitochondrial damage; Oxidative stress

DOI:  https://doi.org/10.1007/s00018-026-06345-4
Oncogene. 2026 Sep 23.

DDR1 sustains ferroptosis resistance in pancreatic ductal adenocarcinoma via SLC40A1-mediated iron homeostasis.

Chao Song, Luting Zhang, Sheng Xu, Xu-An Wang, Xinyi Zhang, Kai Xuan Cheong, Ganggang Wang, Mengmeng Liu, Yazhou Wang, Yifei Zhang, Taochen He, Kai Ding, Yu Chen, Xin Liang, Bing Zhu, Qianzhi Ni, Wenquan Wang, Jingjing Li, Wenhui Lou, Liang Liu.

Integrated single-cell transcriptomics and clinical analyses reveal elevated DDR1 expression in pancreatic ductal adenocarcinoma (PDAC) tissues, which correlates with poor prognosis. Mechanistically, collagen-activated Discoidin Domain Receptor 1 (DDR1) recruits SHC1 to activate the MAPK/ERK pathway, thereby driving transcriptional upregulation of SLC40A1 via the ERK-MYC axis. SLC40A1, encoding an iron exporter, reduces intracellular labile iron pools, thereby suppressing lipid peroxidation and ferroptosis. Consequently, DDR1 overexpression confers resistance to dihydroartemisinin (DHA)-induced ferroptosis in PDAC cells, characterized by diminished ROS accumulation, mitochondrial shrinkage, and cristae loss. Conversely, DDR1 knockdown or pharmacological inhibition (Dasatinib) sensitizes PDAC cells to DHA. Crucially, combining Dasatinib and DHA treatment synergistically inhibits tumor growth in vivo by reactivating ferroptosis, as evidenced by increased 4-HNE accumulation and decreased Ki67 expression. These findings identify DDR1 as a key regulator of iron metabolism and ferroptosis in PDAC, suggesting that dual targeting of DDR1 and ferroptosis represents a promising therapeutic strategy.

DOI: https://doi.org/10.1038/s41388-026-03980-w
Mol Cell Biochem. 2026 Sep 19.

NRF2 signaling drives chemoresistance in NSCLC and glioblastoma.

Izadora de Souza, Linda Karolynne Seregni Monteiro, Ana Beatriz da Silva Teixeira, Camila Banca Guedes, Karoline Almeida Lima, Cláudio Henrique Dahne de Souza Filho, Izabela Amélia Marques de Andrade, Maria Carolina Clares Ramalho, Beatriz Silva de Oliveira, Mariana Lazarini, Clarissa Ribeiro Reily Rocha.

  Although great advances have been made in cancer treatment, lung cancer and glioblastoma patients continue to present a dismal prognosis, mainly due to drug resistance. Evidence suggests that NRF2 and glutathione (GSH) play a fundamental role in chemotherapy resistance. Notably, GSH depletion by buthionine sulfoximine (BSO) has been demonstrated to sensitize human tumor cells to a wide variety of chemotherapeutic agents. However, the incorporation of BSO into standard chemotherapy regimens lacks a robust clinical rationale. In this study, we aimed to investigate the mechanisms governing differential sensitivity to chemotherapy in lung cancer and glioblastoma cells to identify novel strategies to enhance outcomes in these malignancies. For this purpose, we analyzed several cellular responses in cell lines exhibiting distinct sensitivities to temozolomide (TMZ) and cisplatin. Our findings indicate that the NRF2/GSH pathway plays a crucial role in TMZ and cisplatin resistance and that pharmacological GSH depletion enhances the sensitivity of NRF2-high, chemotherapy-resistant cells to these agents. Furthermore, BSO in combination with TMZ or cisplatin enhanced chemotherapy-induced cytotoxicity and engaged both apoptotic and ferroptosis-related responses in NSCLC cells. These findings provide preclinical evidence supporting further investigation of NRF2/GSH targeting as a strategy to overcome chemotherapy resistance.

Keywords:  Cisplatin; Ferroptosis; Glioma; Lung cancer; NRF2; Temozolomide

DOI:  https://doi.org/10.1007/s11010-026-05747-z
Hum Cell. 2026 Sep 22. pii: 144. [Epub ahead of print]39(10):

The deubiquitinase USP5 mediates anti-PD-L1 resistance in breast cancer by stabilizing FOXM1 to upregulate Nectin2.

Guangyan Li, Zhiyuan Su, Yutong Zhang, Qiguang Du, Zhongkai Xu, He Cui, Jianguo Zhang.

  USP5 is a deubiquitinating enzyme whose role in anti-PD-L1 resistance in breast cancer remains unclear. This study investigated whether USP5 contributes to resistance against the anti‑PD‑L1 antibody (atezolizumab) by regulating the FOXM1/Nectin2 axis. Anti-PD-L1-resistant and lung metastatic mouse models were established, combined with in vitro cellular assays, clinical sample analyses, and bioinformatics approaches. The results showed that USP5 was upregulated in breast cancer and stabilized FOXM1 via deubiquitination, which led to increased Nectin2 expression and resistance to CD8⁺ T cell-mediated killing. Knockdown of USP5 or its pharmacological inhibition with G9 synergized with anti-PD-L1 to suppress tumor growth, an effect that was reversible by Nectin2 overexpression. In conclusion, USP5 promotes breast cancer progression and anti-PD-L1 resistance by deubiquitinating FOXM1, thereby upregulating Nectin2 expression. Targeting USP5 enhances the efficacy of anti-PD-L1 therapy, offering a novel strategy to overcome immunotherapy resistance in breast cancer.

Keywords:  Anti-PD-L1 resistance; Breast cancer; Deubiquitination; FOXM1; Nectin2; USP5

DOI:  https://doi.org/10.1007/s13577-026-01455-4
FASEB J. 2026 Oct 15. 40(19): e72341

Nucleolin Alterations and ROS Production Associate With Sensitivity of AML Cells to Venetoclax.

Kateřina Wolfová, Petra Otevřelová, Barbora Brodská.

  Acute myeloid leukemia (AML) is a heterogeneous disease with large spectrum of specific mutations and gene aberrations. Recently, the Bcl-2 inhibitor Venetoclax, in combination with hypomethylating agents (HMAs), was approved for older (> 65 years) AML patients, as well as for those unfit for intensive induction chemotherapy. In addition to Bcl-2 inhibition, Venetoclax also induces generation of reactive oxygen species (ROS). We demonstrated that distinct fraction exhibiting specific features arises during 24 h of sample exposure to Venetoclax. This fraction displays characteristic preapoptotic markers as mitochondria depolarization and partial Annexin V surface positivity. Moreover, monitoring of ROS showed negative correlation between signals detected using H2DCFDA and CellROX probes pointing to dynamic ROS changes induced by Venetoclax. The addition of HMA (Decitabine) had almost no effect on cell viability or ROS production but caused proliferation arrest in sensitive cells. In our panel of AML cell lines and primary AML samples we have found a correlation between ROS production, markers of apoptosis, and attenuation of Bcl-2 activity after Venetoclax treatment. Level of Mcl-1, another antiapoptotic protein from the Bcl-2 family, was reduced in sensitive cells, but increased in the resistant samples in response to Venetoclax. Moreover, the nucleolar protein nucleolin (NCL), which is frequently overexpressed in AML cells, was significantly deregulated in Venetoclax-treated cells. In particular, both NCL protein level and specific phosphorylation decreased in fractions sensitive to Venetoclax. Our findings suggest that Venetoclax targets distinct cell subpopulation, and that ability of a cell to follow increased ROS drives its response to Venetoclax.

Keywords:  Bcl‐2; Decitabine; Doxorubicin; ROS; Venetoclax; acute myeloid leukemia; nucleolin

DOI:  https://doi.org/10.1096/fj.202504934RR
Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2612523123

IRE1α-XBP1s signaling links lipid homeostasis to hypoxic maladaptation and KRAS inhibitor responses in pancreatic ductal adenocarcinoma.

Yanqing Jiang, Cassidy Pagen, Gusangyu Yin, Zian Zhang, Mai Wang, Carson D Poltorack, Yizheng Xue, Xu Han, Nathan J Coffey, Morgan Brown, Xuanyan Cai, Laura C Kim, Justin M Berg, Chih-Hang Anthony Tang, Yihui Shen, Brian Keith, Chih-Chi Andrew Hu, M Celeste Simon.

  Pancreatic ductal adenocarcinoma (PDAC) is among the most hypoxic human tumors. Because fatty acid (FA) desaturation is oxygen-dependent, hypoxia can limit monounsaturated FA (MUFA) production, increase membrane lipid saturation, and activate endoplasmic reticulum stress responses, including IRE1α-XBP1s. Here, we found that under oxygen- and MUFA-limiting conditions, spliced XBP1 (XBP1s) is upregulated but unexpectedly exerts a cytotoxic rather than cytoprotective role in PDAC cells. This effect did not differ substantially between classical and basal subtypes. In contrast, pharmacologic or genetic XBP1s inhibition had limited effects on tumor growth and apoptosis in vivo, suggesting this cytotoxicity is largely bypassed by factors in the tumor microenvironment. Consistent with our previous findings that cancer-associated fibroblasts supply unsaturated lipids to tumor cells, subcutaneous tumors showed abundant alpha-smooth muscle actin (α-SMA)-positive stroma, supporting the possibility that stromal lipid supply protects tumors from XBP1s-dependent lipotoxicity. Although XBP1s expression increased during PDAC progression, its distribution remained focal and heterogeneous within human tumors, suggesting spatially restricted IRE1α-XBP1s pathway activation that may limit the efficacy of monotherapy in patients. However, MRTX1133-resistant PDAC became more susceptible to IRE1α-XBP1s targeting, and MRTX1133 acutely activated this pathway in parental cells upon treatment. Importantly, the IRE1α RNase inhibitor B-I09 clearly synergized with MRTX1133 in vitro and in vivo, moreover, this is likely due to MYC-fatty acid synthase (FASN) dysregulation. Together, these findings identify context-dependent vulnerabilities of the IRE1α-XBP1s pathway in PDAC and provide a rationale for combining inhibition of IRE1α and KRAS to enhance therapeutic responses.

Keywords:  ER stress responses; KRAS inhibitors; hypoxia; lipid metabolism

DOI:  https://doi.org/10.1073/pnas.2612523123
Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2607452123

Mitochondrial NADP(H)-dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors.

Qing Li, Tong Shu, Chen Liu, Min Zheng, Yuanpei Li, Lei Zhang, Gao Fan, Wenbin Lu, Huiwen Zhang, Pingping Liu, Xiaoniu He, Hong Zheng, Wen Liu, Jing Ye, Zhenyu Yin, Xianming Deng, Chensong Zhang, Canhua Huang, Han You.

  PARP inhibitors (PARPis), known to elicit mitochondrial protection in nononcological diseases by elevating the cellular NAD+ pool, exhibit potent cytotoxicity in selected human cancers. The role of mitochondrial metabolism in PARPi-mediated antitumor therapy remains unexplored. Here, we propose a causal link between mitochondrial NAD+ metabolism and PARPi responsiveness. In PARPi-non-responsive tumor cells, PARP inhibition specifically expands mitochondrial NADP(H) [mito-NADP(H)] pool, thereby facilitating de novo mitochondrial dTMP (mito-dTMP) biosynthesis and maintaining mitochondrial dTTP (mito-dTTP) pool to prevent uracil misincorporation into mitochondrial DNA (mtDNA), regardless of homologous recombination (HR) status. Mechanistically, loss of PTPN1 ADPRylation by PARPi abolishes its phosphatase activity toward STAT3, yielding enhanced STAT3 phosphorylation and the subsequent transactivation of FoxO1. FoxO1 modulates transcriptomic signature governing mitochondrial NADPH fluxes to de novo mito-dTMP generation. Our results uncover a fundamental vulnerability that can be leveraged by cotargeting STAT3 and PARP to trigger mitochondrial dysfunction.

Keywords:  PARPi resistance; de novo mitochondrial dTMP biosynthesis; mitochondrial NAD+ metabolism

DOI:  https://doi.org/10.1073/pnas.2607452123
Urol Oncol. 2026 Sep 19. pii: S1078-1439(26)00705-2. [Epub ahead of print]44(11): 897-910

The AURKA-PTTG1 signaling axis induces enzalutamide resistance in prostate cancer.

Guangye Han, Zhenhui Li, Weihang Song, Lei Li, Junling Hu.

   BACKGROUND: Prostate cancer (PCa), a common male malignant tumor, often develops resistance to the androgen receptor inhibitor enzalutamide (ENZ). Despite its established oncogenic role, pituitary tumor-transforming gene 1 (PTTG1)'s specific function and regulatory mechanism in ENZ-resistant PCa require investigation.
METHODS: Cell biology assays were employed to evaluate the effects of PTTG1 and Aurora kinase A (AURKA) on cell proliferation, apoptosis, migration, and ENZ resistance. Bioinformatics analysis revealed that the glycolytic signaling pathway was significantly enriched in the PTTG1‑high expression group. Subsequently, the regulatory roles of PTTG1 and AURKA in glycolysis were verified by measuring glycolysis‑related metabolic parameters and changes in the expression of key proteins. The physical interaction between PTTG1 and AURKA was confirmed by predictions from protein-protein interaction databases and validated by co‑immunoprecipitation experiments. After determining the subcellular localization of PTTG1 through cell fractionation assays, we further assessed the effect of AURKA on the serine phosphorylation levels of the purified GFP-PTTG1 fusion protein. All in vitro results were validated in a nude mouse xenograft model using immunofluorescence, immunohistochemistry, and apoptosis detection assays.
RESULTS: In ENZ-resistant PCa cells, PTTG1 was highly expressed, and its phosphorylation was promoted by AURKA, which in turn facilitated its nuclear translocation to activate Wnt signaling and glycolytic metabolism, driving ENZ resistance in PCa. Targeting the AURKA/PTTG1 axis enhanced ENZ sensitivity in a PCa mouse model.
CONCLUSION: The AURKA/PTTG1 axis contributes to ENZ resistance by promoting glycolytic metabolism in PCa cells.

Keywords:  AURKA; Enzalutamide resistance; Glycolytic metabolism; PTTG1; Prostate cancer

DOI:  https://doi.org/10.1016/j.urolonc.2026.08.010
Mol Cell Biochem. 2026 Sep 19.

Integrative multi-omics analysis identifies LIPA as a prognostic hub and ferroptosis regulator in lung adenocarcinoma.

Fan Zhang, Shuai Han, Xiaodong Cao, Dan Pan, Weijie Song.

  Lung adenocarcinoma (LUAD) remains one of the leading causes of cancer mortality, underscoring the urgent need for biomarkers and therapeutic targets rooted in metabolic reprogramming. By integrating multi-omics analyses with experimental validation, we identified 67 lipid metabolism-related genes dysregulated in LUAD and constructed a five-gene prognostic signature via LASSO regression; lower expression of the signature genes correlated with poor survival. Single-cell and spatial transcriptomics revealed cell-type-specific dysregulation of the hub gene LIPA, which was upregulated in monocytes but downregulated in macrophages within the tumor microenvironment. Functional assays demonstrated that LIPA overexpression inhibited tumor proliferation in vitro and suppressed orthotopic tumor growth in vivo, at least in part through a ferroptosis-dependent mechanism involving TXNIP and ALOX5. Virtual screening further identified Castanospermine as a potential LIPA activator; treatment elevated LIPA expression, modulated the CD4+/CD8 + T-cell ratio, and attenuated tumor progression in mice. Collectively, these findings establish LIPA as a critical link between lipid metabolism, ferroptosis, and immune modulation in LUAD, and provide a prognostic signature for risk stratification as well as a candidate compound for targeting lipid metabolic vulnerabilities.

Keywords:  Ferroptosis; LIPA; Lipid metabolism; Lung adenocarcinoma; Single-cell analysis

DOI:  https://doi.org/10.1007/s11010-026-05741-5
Am J Transl Res. 2026 ;18(8): 6612-6626

The role and mechanism of CHST6-mediated lactation modification in lenvatinib resistance in hepatocellular carcinoma cells.

Dongdong Wang, Hongqiang Gao, Li Li.

   BACKGROUND: Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer-related death. Approximately 70% of HCC patients present with advanced-stage disease at the time of diagnosis. Lenvatinib is a standard first-line treatment for HCC; however, the development of drug resistance substantially limits its therapeutic efficacy.
METHODS: Genes associated with lactylation and lenvatinib resistance were identified through bioinformatic analyses. Differentially expressed genes (DEGs) were screened using data from the TCGA-LIHC cohort, the GSE186191 dataset, and a lactylation-related gene datasets. Receiver operating characteristic (ROC) curve analysis, Cox regression analysis, survival analysis, and prognostic evaluation were performed to analyze the association between identified genes and treatment outcomes. After constructing the lenvatinib-resistant MHCC97 cell line (MHCC97-LR) was established, and the effects of CHST6 knockdown on cell viability, apoptosis, cell cycle, lactate content, and the expression of lactylation-related genes were analyzed.
RESULTS: A total of 15 overlapping DEGs related to both lactylation and lenvatinib resistance were identified. These genes were involved in multiple metabolic pathways, including lipid and glucose metabolism. CHST6, SPAG4, and PFKFB4 exhibited excellent diagnostic performance for HCC, and their lower expression levels were correlated with favorable prognosis. Cox regression analysis identified CHST6 as the only gene significantly associated with HCC prognosis, demonstrating predictive value for 1-5-year survival in HCC patients. Strikingly, enhanced lactylation was associated with elevated CHST6 expression and greater cell viability in MHCC97-LR cells. Furthermore, CHST6 knockdown reduced the lactate production and the expression of lactylation-associated proteins (Pan-Kla, H3K18la, and H3K56la) in MHCC97-LR cells, along with increased apoptosis and G1-phase cell-cycle arrest in MHCC97-LR cells.
CONCLUSION: CHST6 knockdown reduces intracellular lactate contents and lactylation in MHCC97-LR cells, thereby attenuating lenvatinib resistance and enhancing the antitumor efficacy of lenvatinib in HCC.

Keywords:  CHST6; Hepatocellular carcinoma; MHCC97; lactylation modification; lenvatinib resistance

DOI:  https://doi.org/10.62347/JQSF1666
Nat Commun. 2026 Aug 25. pii: 10147. [Epub ahead of print]17(1):

SPOP-mediated ZMYND8 ubiquitination and phase separation exclusion drives mTOR inhibitor resistance in kidney cancer.

Bo Tang, Rui Sun, Jingwei Shao, Qi-You Wu, Yuqian Yan, Dejie Wang, Zhixian Yu, Lianxin Hu, Yicheng Chen, Chengheng Liao, Qiang Wei, Yige Bao, Haojie Huang.

mTOR inhibitors including everolimus and temsirolimus have been approved by US FDA for treatment of clear cell renal cell carcinoma (ccRCC) in clinic. However, resistance to these drugs has been inevitable and the underlying mechanism remains poorly understood. Histone modifier ZMYND8 paradoxically acts as a transcription coactivator or corepressor. Here we show that SPOP, a CULLIN3-RING E3 ubiquitin ligase (CRL) substrate-binding protein that is often overexpressed in ccRCC in patients, promotes K63-linked polyubiquitination of ZMYND8 at lysine 398, which inhibits ZMYND8 to form phase separation compartments and drives the formation of ZMYND8-ZHX2 transactivation complex, resulting in aberrant NEK7 kinase gene transcription, alternative activation of p70S6K, and mTOR inhibitor-resistant cell growth. Inhibition of either SPOP or NEK7 increases ccRCC cell sensitivity to mTOR inhibitor. Treatment with a NEK7 proteolysis-targeting chimera (PROTAC) effectively inhibits aberrant p70S6K activation and overcame everolimus resistance in ccRCC cells in vitro and in mice. Our findings uncover a function switch of ZMYND8 driven by overexpressed SPOP as a key mechanism that causes mTOR inhibitor resistance and nominate NEK7 as a potential target of thwarting mTOR inhibitor resistance in ccRCC.

DOI: https://doi.org/10.1038/s41467-026-77043-9
iScience. 2026 Oct 16. 29(10): 117500

Levofloxacin enhances 5-fluorouracil efficacy in colorectal cancer by activating the DDR-TP53-mitochondrial apoptosis axis.

Chenmeng Huang, Chenchen Sun, Han Wang, Ying Wei, Yufei Zhang, Wenfeng Li, Aping Yue, Yajing Yang, Jiajia Wang, Jindan Guo, Zhengxi Hu, Jiangyang Chi, Yongli Fan.

  5-Fluorouracil (5-FU)-based regimens are a cornerstone of colorectal cancer (CRC) chemotherapy. Levofloxacin (LVF), a widely used fluoroquinolone antibiotic, has been reported to exhibit anticancer properties. We investigated LVF's ability to enhance CRC chemosensitivity to 5-FU in cell lines, subcutaneous xenografts (Balb/c-nude mice), and spontaneous intestinal tumors (Apcmin/+ mice). LVF potentiated 5-FU-induced apoptosis in vitro and in vivo. Mechanistically, LVF induced mitochondrial dysfunction in CRC cells, marked by reactive oxygen species (ROS) accumulation, increased mitochondrial ROS, and loss of mitochondrial membrane potential. TP53 and downstream effectors NOXA and BBC3 mediate between LVF-induced mitochondrial damage and 5-FU sensitization. LVF-induced DNA damage response (DDR) and subsequent oxidative phosphorylation (OXPHOS) upregulation trigger mitochondrial damage and TP53 activation. Importantly, we confirmed that the canonical LVF target TOP2A and the reported LVF effector ribosomal S6 kinase 4 (RSK4) are dispensable for LVF-mediated sensitization. Thus, LVF acts as a non-canonical 5-FU chemosensitizer in TP53-WT CRC via DDR-TP53-mitochondrial apoptosis activation, supporting clinical repurposing.

Keywords:  5-fluorouracil; DNA damage; apoptosis; colorectal cancer; levofloxacin

DOI:  https://doi.org/10.1016/j.isci.2026.117500
Biochimie. 2026 Sep 23. pii: S0300-9084(26)00231-2. [Epub ahead of print]

Sphingolipids as central regulators of therapy resistance and immunity in lung cancer.

Morgane Paque, Anisa Aliju, Arnaud Blomme.

  Lung cancer remains the deadliest cancer worldwide, with most patients exhibiting poor responses to current therapies and rapidly developing treatment resistance. Cancer cells can acquire resistance by rewiring their metabolism. In particular, dysregulated lipid metabolism promotes therapy resistance in multiple cancer types, including lung cancer. In addition to their role in shaping cell membrane, sphingolipids have recently emerged as key mediators of intra- and extracellular communication, triggering oncogenic signaling pathways and affecting immune cell functions. Through the accumulation of specific intermediates, such as ceramide derivatives, dysregulated sphingolipid metabolism can directly influence cell fate, ultimately promoting therapy resistance and immune escape. Consequently, sphingolipids are now considered as major regulators of resistance to chemo-, radio-, and immune checkpoint inhibition therapy. In this review, we will give an overview of the mechanisms by which sphingolipids orchestrate drug resistance and tumor immunity in lung cancer. We will also discuss the potential of targeting sphingolipid metabolism as a promising therapeutic strategy in lung cancer.

Keywords:  immune tumor microenvironment; lipid metabolism; lung cancer; sphingolipids; treatment resistance

DOI:  https://doi.org/10.1016/j.biochi.2026.09.012
Biochim Biophys Acta Mol Basis Dis. 2026 Sep 23. pii: S0925-4439(26)00339-X. [Epub ahead of print]1873(2): 168473

Obesity associated elevated leptin might contribute to paclitaxel resistance via PLCB1/IP3R1 axis in head and neck cancers.

Fatma Sanli, Betul Gundogdu, Omer Faruk Karatas.

   BACKGROUND: Head and neck cancer (HNC) is a heterogeneous malignancy with limited therapeutic success, largely due to its complex pathogenesis and high chemoresistance. Paclitaxel is commonly used in HNC therapy; however, the frequent development of resistance reduces its efficacy. Obesity has been linked to cancer progression, and leptin, an adipokine elevated in obesity, has emerged as a potential mediator of treatment resistance.
METHODS: To explore leptin's role in paclitaxel resistance, taxol-resistant HNC cell lines were treated with leptin. Tumor tissues from obese and non-obese HNC patients were examined by immunohistochemistry to evaluate leptin, phospholipase C beta 1 (PLCB1), and inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) expression. The effect of PLCB1 inhibition on IP3R1 expression, apoptosis, and cell viability was analyzed using functional assays.
RESULTS: Leptin treatment enhanced paclitaxel resistance and modulated the PLCB1-IP3R1 signaling pathway in HNC cells. Pharmacological inhibition of PLCB1 increased IP3R1 expression, promoted apoptosis, and decreased cell viability.
CONCLUSION: Leptin contributes to paclitaxel resistance in HNC through activation of the PLCB1/IP3R1 axis. Targeting this signaling pathway may represent a promising therapeutic approach to overcome chemoresistance, particularly in obese patients with HNC.

Keywords:  Chemoresistance; Head and neck cancer; IP3R1; Leptin; Obesity; PLCB1; Paclitaxel

DOI:  https://doi.org/10.1016/j.bbadis.2026.168473
Cancer Res Commun. 2026 Sep 21.

Integrated genetic screening identifies FEN1 as a selective vulnerability and temozolomide resistance mediator in glioblastoma stem cells.

Benjamin A Brakel, Dillon McKenna, Anish Puri, Muhammad Vaseem Shaikh, Manoj Singh, Ali Saleh, Abdo-Jose Tomajian, Nicholas Mikolajewicz, Marcello Beltrami, Maxwell Topley, Alisha Anand, Petar Miletic, Kevin R Brown, David Tieu, William Maich, Sabra Salim, Yujin Suk, Minomi Subapanditha, Deena M A Gendoo, Chitra Venugopal, Jason Moffat, Sachin Katyal, Chirayu R Chokshi, Sheila K Singh.

Glioblastoma (GBM) is an aggressive brain tumor characterized by therapy resistance and recurrence. Glioblastoma stem cells (GSCs) are key drivers of tumor maintenance, therapeutic resistance, and relapse, but targeting them remains clinically elusive due to their overlap with normal neural stem cells (NSCs) and a lack of actionable vulnerabilities. To identify selective vulnerabilities in GSCs, we performed genome-wide CRISPR-Cas9 loss-of-function screening across patient-derived GSC models under standard-of-care treatment conditions. We identified flap endonuclease 1 (FEN1), a key enzyme in DNA replication and base excision repair, as an essential gene for GSC survival, with enhanced dependency in the context of temozolomide (TMZ) treatment. Genetic knockdown of FEN1 impaired GSC proliferation and self-renewal and extended survival in a patient-derived xenograft model. Pharmacologic inhibition of FEN1 using a small-molecule inhibitor revealed selective cytotoxicity in highly aggressive and recurrent GBM models, while sparing NSCs. Notably, FEN1 inhibition synergized with TMZ to induce DNA double-strand breaks and potentiate cell death only in a subset of GSCs sensitive to FEN1 inhibition. Mechanistically, single-cell transcriptomics revealed that FEN1 expression correlates with programs linked to proliferation, stemness, and DNA damage repair, underscoring its role in maintaining the treatment-refractory phenotype. Our findings identify FEN1 as a selective vulnerability in aggressive, proliferative GSCs. FEN1 inhibition not only impairs GSC viability but also restores sensitivity to TMZ in treatment-resistant models, offering a strategy for salvage therapy in recurrent GBM. These results support the development of FEN1-targeted therapies and lay the foundation for a biomarker-guided approach to overcome chemoresistance in GBM.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0150
RSC Adv. 2026 Sep 22.

Sorafenib-loaded porphyrin-phospholipid liposomes for enhanced chemophototherapy in hepatocellular carcinoma.

Meiling Tian, Jing Wang, Ming Gao, Chaoyuan Xia, Jing Xiao, Yi Zhao, Bingjie Han, Ningjing Lei, Siyuan Huang, Baihui Xie, Lulu He, Fazhan Wang, Shengnan Ma, Bo Qin.

Sorafenib (SF) remains a frontline chemotherapeutic agent for treating hepatocellular carcinoma (HCC). However, its clinical utility is severely hampered by systemic toxicity and the rapid emergence of drug resistance. To overcome these challenges, we developed a liposomal nanoplatform co-encapsulating SF and a porphyrin-phospholipid conjugate (2HPoP) for combined chemo-photodynamic therapy. The synthesized SF-loaded 2HPoP liposomes (2HPoP lip@SF) exhibited favorable physicochemical characteristics, including high encapsulation efficiency, colloidal stability, and prolonged storage stability. Upon 665 nm red-light laser irradiation, 2HPoP lip@SF demonstrated controlled drug release and robust reactive oxygen species (ROS) generation, enabling synergistic antitumor effects. In vitro, 2HPoP lip@SF combined with red-light laser irradiation significantly reduced the viability of liver cancer cells, demonstrating a superior eminent therapeutic effect compared to the free SF at equivalent concentrations. In addition, 2HPoP lip@SF with laser irradiation showed more effective tumor shrinkage than equivalent chemotherapy and PDT monotherapies in a mouse model of human HCCLM3 tumors. In summary, we present a facile yet effective strategy for co-delivering SF and a photosensitizer within a single liposomal system. The 2HPoP lip@SF formulation not only enhances therapeutic efficacy but also provides a clinically translatable approach for improving HCC treatment outcomes.

DOI: https://doi.org/10.1039/d6ra05195b
Signal Transduct Target Ther. 2026 Sep 21. pii: 393. [Epub ahead of print]11(1):

BCLXL blockade rewires cell fate to overcome PARP inhibitor resistance in ovarian cancer.

Annapoorna Venkatachalam, Annabella R Strathman, Xianon Hou, Cristina Correia, X Wei Meng, Cordelia D McGehee, Emily A Balczewski, Laura N Duffield, Olivia K Rossman, Clara Wong, Haiming Dai, Rachel M Hurley, Jill M Wagner, Saloni Singh, Karen S Flatten, Kevin L Peterson, Paula A Schneider, Silvana B De Lorenzo, Melissa C Larson, Ann L Oberg, Andrea E Wahner Hendrickson, Xinyan Wu, Akhilesh Pandey, Hu Li, S John Weroha, Scott H Kaufmann.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) induce regressions and extend progression-free survival (PFS) in ovarian cancer, especially in tumors with BRCA1 or BRCA2 mutations that impair homologous recombination repair. While recent studies have clarified the key roles of BRCA1, BRCA2, and PARP1 in replication fork stability, the downstream mechanisms that mediate PARPi-induced cytotoxicity and resistance remain incompletely understood. Here we delineate cell fate outcomes following PARPi treatment in homologous recombination-deficient high-grade serous ovarian cancer and identify actionable pathways to overcome acquired resistance. Our findings reveal that PARPi-induced DNA damage simultaneously triggers apoptosis, which primarily occurs through the BAX/BAK-dependent intrinsic apoptotic pathway, while also driving cellular senescence, as manifested by the expression of senescence-associated β-galactosidase, CDKN1A upregulation and a senescence-associated secretory phenotype. Notably, the PARPi-induced senescent cells persist as resistance develops and exhibit multinucleation, a hallmark of nuclear atypia, both in vitro and in patient-derived xenografts (PDXs). Building on the observation that the anti-apoptotic protein BCLXL restrains pro-apoptotic BCL2 family members after PARPi treatment, we show that addition of the BCLXL inhibitor A-1155463 to PARPi therapy diminishes resistance in multiple high-grade serous ovarian cancer cell lines in vitro and significantly enhances PARPi-induced tumor response in a PDX model with acquired PARPi resistance in vivo. Overall, these preclinical findings strongly support the potential of combining BH3 mimetics with PARPis to treat resistant ovarian cancer.

DOI: https://doi.org/10.1038/s41392-026-02870-7