bims-meract 2026-04-19 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–04–19
twenty-two papers selected by
Andrea Morandi, Università degli Studi di Firenze

Aberrant activation of epigenetic BRD9-DGAT1 axis promotes lipid droplets deposition and ferroptosis resistance in YAP-high prostate cancer.
Analysis of metabolic rewiring in MDR1-overexpressing drug-resistant glioblastoma.
The KRT15 and KRT81 complex promotes lenvatinib resistance in thyroid cancer by upregulating DGKB mediated lipid metabolism.
Lactate-driven pyrimidine synthesis promotes ferroptosis resistance in hepatocellular carcinoma.
PGK1/PHGDH axis drives radioresistance in glioblastoma stem cells.
Hypoxia Induces a Mitotic Survival Advantage After Radiotherapy in Head and Neck Cancer Cells.
Mitochondrial superoxide sustains a senescence-like phenotype in PARP- inhibited ovarian cancer cells by stabilizing HIF1α.
Suppression of Glucosylceramide Synthase Reverses Drug Resistance in Cancer Cells Harboring Homozygous p53 Mutants.
Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.
Suppression of Tumor Aggression Through Metabolic Reprogramming via Oxamate Targeting LDHA.
Altered Sphingolipid Metabolism is Associated with Osimertinib Resistance in Nonsmall-Cell Lung Cancer.
FAAH initiates a positive feedback loop to promote lung adenocarcinoma progression through inhibition of ferroptosis.
Diet-induced metabolic memory shapes CD8+ T cell ferroptosis susceptibility.
Extracellular ATP promotes endocrine resistance in ER+ breast cancer through upregulation of PYGL.
SCD1 and SCD5 modulate PARP-dependent DNA repair via fatty acid desaturation in glioblastoma.
ATR and PKMYT1 inhibition re-sensitize a subset of TNBC patient-derived models to carboplatin inducing mitotic catastrophe.
Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance.
SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.
Dual inhibition of glycolysis and glutaminolysis by targeting FOXO3 for hepatocellular carcinoma treatment.
Peroxisome-derived and liver-specific hydroxyacid oxidase 1-mediated hydrogen peroxide promotes ferroptosis by augmenting peroxisomal ROS.
Identification of a Prognostic Gene Signature for Chemoresistance Prediction in Lung Adenocarcinoma by Screening Mitochondrial Metabolism Gene Sets.
Lactate-induced lactylation enhances BMAL1 transcription and nuclear translocation, promoting bevacizumab resistance in glioblastoma through VEGFA.

Cell Death Dis. 2026 Apr 14.

Aberrant activation of epigenetic BRD9-DGAT1 axis promotes lipid droplets deposition and ferroptosis resistance in YAP-high prostate cancer.

Xuejin Zhu, Zhimei Wen, Jinhai Wu, Sian Chen, Ran Xu, Bin Wang, Yingwen Zhu, Yanfei Chen.

Aberrant interplay between epigenetics and metabolism contributes to prostate cancer (PCa) progression and represents a formidable challenge limiting the efficacy of drugs. Elucidation of the epigenetic underpinnings of prostate cancer (PCa) could provide promising insights into the drivers of therapy resistance. Through an unbiased siRNA screen of mSWI/SNF family members, which play a significant role in tumorigenesis, we identified Bromodomain containing 9 (BRD9) as an essential gene for PCa growth. Targeting BRD9 abolished PCa colony formation and migration in vitro, and inhibited orthotopic tumor growth in vivo. YAP/TEAD4 complex bound to the BRD9 promoter to elevate its levels. Integrated CUT&Tag-seq and RNA-seq analyses revealed DGAT1 as an important BRD9 effector. Mechanistically, BRD9 interacted with SREBP1 to co-occupy the DGAT1 promoter, increasing the H3K4me3 enrichment and chromatin accessibility. Additionally, the YAP-BRD9 axis enhanced the lipid droplets (LDs) formation, ferroptosis resistance, and tumorigenesis via inducing DGAT1. The pharmacological inhibition (or depletion) of BRD9 suppressed LDs formation, restored ferroptosis sensitivity, and PCa malignancy. Overall, the BRD9-SREBP1-DGAT1 axis represents a potential epigenetic therapeutic target for YAP-high PCa.

DOI: https://doi.org/10.1038/s41419-026-08746-6
Front Pharmacol. 2026 ;17 1760920

Analysis of metabolic rewiring in MDR1-overexpressing drug-resistant glioblastoma.

Manendra Singh Tomar, Ashutosh Shrivastava, Priyanka Prajapati, Chirag Kulkarni, Sreyanko Sadhukhan, Shashi Kumar Gupta, Naibedya Chattopadhyay, Amit Lahiri.

  Glioblastoma (GBM) is a primary brain tumor, and temozolomide is the first-line alkylating agent utilized as a chemotherapeutic treatment. Despite major improvements in diagnosis and therapy, patient's outcomes remain poor, mostly due to acquired temozolomide resistance. ABC transporter-mediated drug efflux is one of the mechanisms that play a crucial role in temozolomide resistance; however, the metabolic mechanisms that sustain MDR1 (ABCB1) activity in GBM remain unknown. Here, we established stable MDR1-overexpressing GBM cells and demonstrated their functional involvement in drug efflux by decreased intracellular doxorubicin accumulation and increased cell viability. Gas chromatography-mass spectrometry-based untargeted metabolomics profiling identified significantly altered metabolites in MDR1-overexpressing cells. Results of multivariate and univariate statistical analysis revealed higher levels of tricarboxylic acid (TCA) cycle intermediates that are associated with enhanced mitochondrial bioenergetics. Pathway enrichment revealed metabolite alterations in the TCA cycle, amino acid, and glutathione metabolism, indicating a coordinated metabolic rewiring potentially linked to increased ATP demand for MDR1 activity. The annexin V staining showed increased apoptotic cell populations upon metformin treatment, supporting the association between mitochondrial metabolism and intracellular drug accumulation. Overall, this study suggests that mitochondrial metabolism is a bioenergetic driver of MDR1 activity, and it could be a potential therapeutic target for overcoming MDR1-mediated drug resistance in GBM.

Keywords:  ABC transporter; glioblastoma; metabolomics; mitochondrial metabolism; temozolomide resistance

DOI:  https://doi.org/10.3389/fphar.2026.1760920
Sci Rep. 2026 Apr 16.

The KRT15 and KRT81 complex promotes lenvatinib resistance in thyroid cancer by upregulating DGKB mediated lipid metabolism.

Yunjun Wang, Yu Zhang, Dan Zhao, Yi Wu, Tian Liao, Yu Wang, Jun Xiang, Qi Chen, Tuanqi Sun.

  Lenvatinib resistance is a major clinical obstacle in the treatment of radioiodine-refractory papillary thyroid cancer (PTC). Clarification of the molecular mechanisms of this resistance is of utmost importance to devise effective therapeutic strategies. We investigated the role of Keratin 15 (KRT15) in lenvatinib resistance through comprehensive in vitro and in vivo studies. Tumor and normal thyroid tissues were analyzed for KRT15 expression and correlation with patient survival. Metabolic profiling was performed to investigate KRT15-dependent alterations in lipid metabolism, namely fatty acid oxidation (FAO). Mechanistic investigations explored the interaction between KRT15, Keratin 81 (KRT81), and Diacylglycerol Kinase B (DGKB). The therapeutic potential of targeting this pathway was evaluated using shRNA-mediated knockdown and pharmacological inhibition. KRT15 overexpression was associated with unfavorable clinical prognosis in thyroid cancer patients. We identified that KRT15 interacts with KRT81 to constitute a regulatory complex, which induces DGKB upregulation. The KRT15-KRT81-DGKB axis controls metabolic reprogramming by upregulating key FAO enzymes (CPT1A and ACOX1), resulting in increased cellular energetics and survival against therapeutic stress. Inhibition of this pathway successfully restored lenvatinib sensitivity in resistant cells. This study illustrates a novel mechanism of cytoskeletal proteins involvement in metabolic adaptation of drug-resistant thyroid cancer cells. The KRT15-KRT81-DGKB pathway is a promising therapeutic target, particularly in combination with lenvatinib, for refractory thyroid cancer patients.

Keywords:  DGKB; KRT15; KRT81; Lenvatinib resistance; Lipid metabolism; Thyroid cancer

DOI:  https://doi.org/10.1038/s41598-026-47994-6
Mol Biomed. 2026 Apr 17. pii: 53. [Epub ahead of print]7(1):

Lactate-driven pyrimidine synthesis promotes ferroptosis resistance in hepatocellular carcinoma.

Mun-Ju Park, Sebin Lee, Dong-Ho Kim, Mi Kyung Kim, Byoung Kuk Jang, Ghilsuk Yoon, Mihyang Park, Gui-Hwa Jeong, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.

  Hepatocellular carcinoma (HCC) remains highly lethal, and emerging therapeutic strategies increasingly focus on harnessing ferroptosis to overcome treatment resistance. However, ferroptosis resistance has emerged as a major barrier to these approaches, highlighting the need to identify metabolic cues in the tumor microenvironment that drive this evasion. Here, we identify lactate as a critical metabolite that mediates detrimental metabolic crosstalk between HCC cells and hepatic stellate cells (HSCs), coupling this interaction to pyrimidine biosynthesis and enhanced extracellular matrix (ECM) production within the tumor microenvironment. We show that tumor-derived lactate activates mechanistic target of rapamycin complex 1 (mTORC1)-carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) signaling, enhancing de novo pyrimidine biosynthesis and pre-ribosomal RNA synthesis, thereby promoting ECM protein translation. The resulting ECM deposition drives Yes-associated protein (YAP)/TEA domain family member (TEAD)-dependent upregulation of the cystine/glutamate antiporter (xCT) in HCC cells, conferring marked resistance to sorafenib-induced ferroptosis. Inhibition of dihydroorotate dehydrogenase, the rate-limiting enzyme in pyrimidine synthesis, disrupts ECM production and restores ferroptosis sensitivity in vitro and in vivo. Clinical data further support these findings, indicating that phosphorylated CAD (p-CAD) levels in HSCs are associated with both poor prognosis and lactate-associated ECM enrichment in HCC patients. Collectively, our study identifies lactate-fueled pyrimidine biosynthesis as a key driver of ECM remodeling and ferroptosis resistance in HCC. Targeting this metabolic axis offers a promising therapeutic strategy to overcome ECM-mediated drug resistance and improve outcomes with ferroptosis-based HCC therapies.

Keywords:  Extracellular matrix; Ferroptosis; Hepatic stellate cells; Hepatocellular carcinoma; Lactate; Pyrimidine biosynthesis

DOI:  https://doi.org/10.1186/s43556-026-00450-3
Cancer Lett. 2026 Apr 15. pii: S0304-3835(26)00280-6. [Epub ahead of print] 218517

PGK1/PHGDH axis drives radioresistance in glioblastoma stem cells.

Zhangchun Cheng, Fangshu Ding, Jianxing Yin, Yingyi Wang, Yapeng Gao, Xin Ge, Junxia Zhang, Xiefeng Wang, Minghui Zhao, Ningwei Zhao, Chuanjun Shu, Xiuxing Wang, Xu Qian, Chunfa Qian, Jing Ji, Yongping You, Zhumei Shi.

  Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, and radiotherapy is a key treatment option. However, glioblastoma stem cells (GSCs) can develop resistance to radiotherapy through metabolic reprogramming, which often results in tumor recurrence. Here we found that glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was phosphorylated at threonine 8 (T8) by ataxia telangiectasia mutated (ATM) upon irradiation (IR), leading to enhanced binding of PGK1 to phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme for the serine synthesis pathway (SSP). PGK1 subsequently functioned as a protein kinase to phosphorylate PHGDH at T60, which resulted in enhanced PHGDH enzymatic activity and increased serine synthesis to fuel the production of S-adenosylmethionine (SAM). Increased SAM then promoted the levels of histone H3K36 trimethylation (H3K36me3) to recruit RAD51 to engage homologous recombination (HR)-mediated DNA damage repair to confer resistance of GSCs to IR. Importantly, both inhibiting PHGDH T60 phosphorylation and suppressing its enzymatic activity sensitized GSCs to IR, inhibited growth of orthotopic xenografts, and prolonged survival of tumor-bearing mice. Furthermore, clinical analysis indicated that phosphorylation levels at both PHGDH T60 and PGK1 T8 corresponded closely with the poor prognosis of GBM patients. This study revealed an ATM-PGK1-PHGDH signaling axis that promotes serine synthesis to confer resistance of GSCs to IR, and suggested that targeting PHGDH may serve as a potential strategy to overcome radioresistance in GBM.

Keywords:  GSCs; PGK1; PHGDH; SAM; radioresistance; serine

DOI:  https://doi.org/10.1016/j.canlet.2026.218517
Int J Cancer. 2026 Apr 13.

Hypoxia Induces a Mitotic Survival Advantage After Radiotherapy in Head and Neck Cancer Cells.

Marilyn Wegge, Rüveyda Dok, Ludwig J Dubois, Sandra Nuyts.

  Hypoxia is an important cause of radiotherapy resistance in head and neck cancers. Cancer cells adapt to hypoxic conditions through various molecular alterations, leading to treatment resistance and tumor progression. A deeper understanding of these hypoxia-induced molecular alterations is essential for future development of effective hypoxia targeting and radiosensitizing therapies. In this study, we tracked (post-)hypoxic cells at single-cell level in HPV-negative and HPV-positive HNSCC models using a hypoxia fate mapping system. We found that (post-)hypoxic cells drive regrowth after radiotherapy in 3D conditions and showed an increased resistance to radiation. Transcriptomic analysis showed that post-hypoxic cells are characterized by a gene expression signature mainly defined by checkpoint regulation. Consistent with these findings, radiotherapy resistant post-hypoxic cells showed a reduced number of radiotherapy-induced micronuclei and mitotic spindle aberrations, indicating a mitotic survival advantage. Inhibition of mitotic checkpoint proteins ATR and CHK1/2 increased the radiosensitivity of post-hypoxic cells. In conclusion, our findings indicate that radiotherapy resistance in HNSCC cells is associated with mitotic survival advantage of post-hypoxic cells, independent of HPV-status.

Keywords:  head and neck cancer; human papillomavirus; hypoxia; mitosis; radiotherapy

DOI:  https://doi.org/10.1002/ijc.70479
Redox Biol. 2026 Apr 07. pii: S2213-2317(26)00156-4. [Epub ahead of print]93 104158

Mitochondrial superoxide sustains a senescence-like phenotype in PARP- inhibited ovarian cancer cells by stabilizing HIF1α.

Tingting Yang, Wenqing Bu, Xiaotong Xue, Xuemin Wu, Yipeng Zhou, Yue Chen, Yanan Li, Jia Zhang, Peishan Li, Fangrong Shen, Yufang Shi, Changshun Shao.

  Ovarian cancer is the deadliest gynecological malignant tumor and is known as the "silent killer". PARP inhibitors are being increasingly used for their excellent efficacy in the treatment of ovarian cancer. While PARP inhibitors are known to interfere with DNA repair and cause DNA damage, the fates of cancer cells and associated metabolic features in response to PARP inhibition are not well characterized. We herein show that ovarian cancer cells treated with PARP inhibitors exhibit a senescence-like phenotype that is characterized by cell cycle arrest, positive staining of senescence-associated β-gal, and increased accumulation of dysfunctional mitochondria. The survival of senescence-like cells is sustained by glycolysis that is driven by an augmented axis of mitochondrial reactive oxygen species (mtROS) and HIF1α. Mitochondrial antioxidant, inhibition of HIF1α activation and restriction of glycolysis can each block the entry into and the sustenance of the senescence-like state in PARP-inhibited ovarian cancer cells. The senescence-like phenotype, HIF1α activation and lactate production were attenuated in tumor xenografts co-treated with PARP inhibitor Rucaparib and mitochondrial antioxidant. The metabolic reliance on mtROS-driven glycolysis in ovarian cancer cells treated with PARP inhibitors has implications in cancer treatment.

Keywords:  Glycolysis; HIF1α; Mitochondrial ROS; Ovarian cancer; PARP inhibitors; Senescence

DOI:  https://doi.org/10.1016/j.redox.2026.104158
Int J Mol Sci. 2026 Apr 02. pii: 3237. [Epub ahead of print]27(7):

Suppression of Glucosylceramide Synthase Reverses Drug Resistance in Cancer Cells Harboring Homozygous p53 Mutants.

Md Saqline Mostaq, Mohammad N Amin, Amanda Raphael, Celine Asbury, Anish Gupta, Xin Gu, Xianlin Han, Davorka Sekulic, Pawel Michalak, Lin Kang, Yong-Yu Liu.

  Glucosylceramide synthase (GCS) catalyzes ceramide glycosylation in response to cell stress that produces glucosylceramide and other glycosphingolipids. GCS overexpression is a cause of drug resistance and enriches cancer stem cells (CSCs) during cancer chemotherapy. Previous studies showed that GCS modulates the expression of p53 mutants and oncogenic gain-of-function (GOF) in heterozygous knock-in cell models (TP53 R273H-/+). However, it is unclear whether GCS can modulate the effects of homozygous p53 mutations, which are common in many cancer cases. We report herewith that inhibition of GCS, via UGCG knockout and using an inhibitor (Genz-161), effectively re-sensitizes drug resistance and diminishes CSCs in colon cancer cells carrying the homozygous p53 R273H mutation. In aggressive WiDr cells carrying TP53 R273H mutation, knockout of UGCG gene using CRISPR/Cas9 editing or inhibition of GCS with Genz-161 sensitized cancer cells to oxaliplatin, irinotecan and paclitaxel. With decreased ceramide glycosylation in lipidomic profiling, both UGCG knockout and Genz-161 treatments substantially decreased wound healing, and diminished CSCs and tumor growth under chemotherapy. Interestingly, inhibition of RNA m6A methylation by neplanocin A markedly increased p53 function and reversed drug resistance. Mechanistic investigation revealed that GCS inhibition downregulated methyltransferase-like 3 (METTL3) expression and decreased RNA-m6A modification on mutant p53 R273H effects. Altogether, our findings demonstrate that ceramide glycosylation promotes METTL3 expression and RNA m6A methylation in response to drug-induced stress, thereby promoting mutant p53 expression and associated GOF. Conversely, inhibition of GCS can diminish CSCs and drug resistance via reduction in m6A modification and advance of p53-assocaited tumor suppressive function. GCS inhibition is an achievable approach for mutant cancer treatment.

Keywords:  N6-methyladenosine; RNA modification; cancer stem cells; drug resistance; glucosylceramide synthase; missense mutation; p53 tumor suppressor

DOI:  https://doi.org/10.3390/ijms27073237
Blood Neoplasia. 2026 May;3(2): 100196

Acid ceramidase inhibition enhances BCL-2 targeting in venetoclax-resistant acute myeloid leukemia.

Johnson Ung, Su-Fern Tan, Jeremy J P Shaw, Maansi Taori, Tess M Deddens, Giovana Venancio, McLane M Montgomery, James T Hagen, Raphael T Aruleba, Upendar R Golla, Arati Sharma, B Bishal Paudel, Irene Lee, Bhavishya Ramamoorthy, Kevin A Janes, Francine Garrett-Bakelman, Myles C Cabot, Kelsey H Fisher-Wellman, Todd E Fox, David F Claxton, Charles E Chalfant, David J Feith, Thomas P Loughran.

Resistance to combination regimens containing the B-cell lymphoma 2 (BCL-2) inhibitor and BH3 mimetic venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively used agent. We previously established the antileukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML, and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supports leukemic survival and resistance to BH3 mimetics. Here, we report the antileukemic efficacy and mechanisms of cotargeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML data set revealed a positive relationship between increased AC gene expression and venetoclax resistance. Pharmacologic AC inhibition with the ceramide analog SACLAC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was synergistically lethal when evaluated ex vivo across a cohort of venetoclax-resistant (n = 21) and venetoclax-sensitive (n = 46) primary samples from patients with AML. Moreover, the SACLAC + venetoclax combination was equipotent to the combination of venetoclax + cytarabine at reducing cell viability across primary patient samples. Mechanistically, cotargeting AC and BCL-2 increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Importantly, AC knockdown sensitized AML cells to venetoclax and induced NOXA protein accumulation, whereas NOXA knockdown protected against AC and BCL-2 cotargeting. Collectively, these findings demonstrate the efficacy of cotargeting AC and BCL-2, and rationalize targeting AC as a therapeutic approach for venetoclax-sensitive and -resistant AML.

DOI: https://doi.org/10.1016/j.bneo.2026.100196
Int J Mol Sci. 2026 Apr 02. pii: 3245. [Epub ahead of print]27(7):

Suppression of Tumor Aggression Through Metabolic Reprogramming via Oxamate Targeting LDHA.

Yurii V Stepanov, Galyna I Solyanik, Yulia Yakshibaeva, Denis Kolesnik, Liudmyla I Stepanova, Iuliia Golovynska.

  Lactate dehydrogenase (LDH) is a key glycolytic enzyme that catalyzes the interconversion of pyruvate and lactate, with LDHA gaining particular attention for its overexpression in various malignancies and pivotal role in the Warburg effect-driven metabolic reprogramming. Elevated LDHA activity supports rapid ATP production under hypoxic conditions, maintains NAD+ regeneration, and promotes lactate accumulation, creating an acidic tumor microenvironment (TME) that favors invasion and immune evasion. Accumulating evidence demonstrates that LDHA is essential for primary tumor growth and critically involved in circulating tumor cell (CTC) survival, anoikis resistance, and metastatic spread. These functions are mediated by its regulation of adhesion molecules, cytoskeletal remodeling, and energy adaptation that enable CTCs to withstand mechanical shear stress and immune surveillance in the bloodstream. Pharmacological inhibition of LDHA, particularly via sodium oxamate (oxamate), has shown substantial potential in reducing metastasis and enhancing chemotherapy sensitivity in preclinical models. Oxamate has emerged as a promising candidate for metabolic cancer therapy due to its unique double effects on tumor metabolism and anti-tumor immunity, which are an advantage rarely highlighted in broader LDHA-focused reviews. This review synthesizes the molecular mechanisms through which LDHA drives tumor progression, dissects its context-specific functions in CTC biology, and evaluates the translational potential of LDHA-targeted strategies, with a focused emphasis on oxamate, as a transformative anti-metastatic therapeutic paradigm. By filling a critical gap in synthesizing oxamate's distinct metabolic-immune regulatory actions, this work addresses an unmet need in the management of advanced, treatment-refractory cancers.

Keywords:  anoikis resistance; blockade of glycolysis; cancer metabolism; circulating tumor cells; invasion; lactate dehydrogenase; metastasis; migration; sodium oxamate

DOI:  https://doi.org/10.3390/ijms27073245
J Proteome Res. 2026 Apr 16.

Altered Sphingolipid Metabolism is Associated with Osimertinib Resistance in Nonsmall-Cell Lung Cancer.

Julia Babuta, Aleksandra Gruevska, Chiharu Wickremesinghe, Alex Montoya, Georgia Roumelioti, Pavel Shliaha, Cristina Balcells, Flora McKinney, Chandler Bray, Toby Athersuch, Matthew Martin, Hector Keun, Zoe Hall.

  Nonsmall-cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases. Epidermal growth factor receptor mutations (EGFRm) occur in 15 and 40% of NSCLC in Western and Asian populations, respectively. Current treatment for advanced NSCLC targets EGFRm with tyrosine kinase inhibitors (TKIs). Osimertinib is a third-generation EGFR-TKI now used as a first-line treatment in advanced/metastatic NSCLC; however, drug resistance frequently develops. Dysregulation of metabolism has been suggested to play a role in the development of drug resistance. Here, we investigated the role of lipid metabolism in the development of osimertinib resistance (OR) using pharmacologically-induced resistant cellular models. We used a multiomics approach, combining lipidomics with proteomics analyses. We found alterations in processes relating to metabolism, such as dysregulated sphingolipid metabolism. In particular, we identified that OR lines reduce free ceramides in favor of complex glycosphingolipids. Mechanistically, this metabolic shift avoids ceramide-mediated apoptosis via caspase-3 activation. Importantly, when we combined osimertinib with D-PDMP, an inhibitor of the key enzyme responsible for the conversion of ceramide to glucosylceramide, we increased the sensitivity to osimertinib. Overall, we have identified the glycosphingolipid metabolic pathway as a potential therapeutic target to reinstate sensitivity to osimertinib in NSCLC.

Keywords:  ceramide; glucosylceramidase; glycosphingolipid; lipidomics; multiomics; nonsmall-cell lung cancer; sphingolipid, drug resistance

DOI:  https://doi.org/10.1021/acs.jproteome.6c00216
Cell Death Differ. 2026 Apr 17.

FAAH initiates a positive feedback loop to promote lung adenocarcinoma progression through inhibition of ferroptosis.

Xinyi He, Cheng Tang, Tongtong Jiang, Chaohao Yang, Xiang Zhang, Zhuan Ju, Jiuzhou Zhao, Renji Wei, Ting Wang, Yanlu Xiong, Lintao Jia, Xiao Zhang.

Ferroptosis represents an iron-dependent form of cell death characterized by accumulation of lipid peroxides. However, it is largely elusive how authentic lipid metabolites contribute to ferroptosis, and whether this is dysregulated in malignant cells due to metabolic rewiring. Here, we identify fatty acid amide hydrolase (FAAH) as a crucial ferroptosis regulator in lung adenocarcinoma (LUAD). FAAH is upregulated and correlated with poor prognosis of LUAD patients. FAAH overexpression inhibits ferroptosis, whereas FAAH knockdown robustly enhances ferroptosis of LUAD cells. Mechanistically, FAAH promotes the palmitoylation of STAT3 through converting N-palmitoylethanolamine to palmitic acid. Palmitoylated STAT3 undergoes cytomembrane translocation and phosphorylation by JAK2, and transcriptionally activates GPX4 to suppress ferroptosis. Concomitantly, activated STAT3 licenses FAAH transcription, thus forming a positive feedback loop in LUAD cells. FAAH targeting represses tumor growth and boosts the anti-tumor efficacy of cisplatin in vivo. These findings uncover a novel regulatory circuit of ferroptosis driven by a saturated fatty acid, and demonstrate the applicability of targeting FAAH to overcome ferroptosis resistance in LUAD therapy.

DOI: https://doi.org/10.1038/s41418-026-01742-5
Nat Immunol. 2026 Apr 13.

Diet-induced metabolic memory shapes CD8+ T cell ferroptosis susceptibility.

Ryan P Mansell, Whitney S Henry.

DOI: https://doi.org/10.1038/s41590-026-02493-8
Cell Death Dis. 2026 Apr 13.

Extracellular ATP promotes endocrine resistance in ER+ breast cancer through upregulation of PYGL.

Yu-Qing Yu, Xin-Yao Yu, Xiao-Fei Li, Yi-Fan Cheng, Yan-Ting Zhou, Fang Mei, Liang Weng, Xin-Xia Tian.

Hormone receptor (HR)-positive breast cancer accounts for approximately 60% of all breast cancer cases, for which endocrine therapy represents the mainstay of treatment; however, the development of therapeutic resistance substantially limits its clinical efficacy. Extracellular adenosine 5'-triphosphate (ATP) has been implicated as a key mediator of metastasis and chemotherapy resistance in multiple malignancies, including breast cancer, yet its role in endocrine resistance remains poorly defined. Here, we demonstrate that extracellular ATP upregulates glycogen phosphorylase L (PYGL) expression in ER-positive breast cancer cells following endocrine treatment, thereby promoting endocrine resistance. Mechanistically, extracellular ATP activates the P2Y12-AhR signaling axis, leading to increased PYGL expression, enhanced glycolytic activity, and subsequent resistance to endocrine therapy. Moreover, elevated PYGL expression was strongly associated with reduced endocrine therapy sensitivity in breast cancer organoids and clinical tumor specimens. Collectively, these findings identify extracellular ATP-driven PYGL activation as a critical mechanism underlying endocrine resistance and suggest that targeting this pathway may represent a promising strategy to improve endocrine therapy efficacy in breast cancer patients.

DOI: https://doi.org/10.1038/s41419-026-08736-8
Cell Rep. 2026 Apr 13. pii: S2211-1247(26)00301-3. [Epub ahead of print]45(4): 117223

SCD1 and SCD5 modulate PARP-dependent DNA repair via fatty acid desaturation in glioblastoma.

Hayk Mnatsakanyan, Alessandro Sammarco, Abigail Hewett, Rami Awwad, Elie Roumieh, Caline Pechdimaljian, Cagri Cakici, Caroline M Spangler, Yana Azar, Richa Pradhan, Baolong Su, Kevin J Williams, Steven J Bensinger, Christian E Badr.

  Glioblastoma (GBM) relies on fatty acid metabolism for aggressive growth. This study identifies stearoyl-CoA desaturase-5 (SCD5), a brain-enriched isoform, as a critical driver of glioblastoma stem cell (GSC) maintenance and genomic stability. While SCD1's role in GBM is well-established, our research reveals that SCD5 plays a non-redundant role by preferentially desaturating C18:0 and uniquely remodeling sphingolipids. Genetic silencing of SCD5 disrupts the cell cycle, impairs DNA repair, and triggers parthanatos-a form of cell death caused by PARP1 hyperactivation. Mechanistically, loss of SCD activity or saturated fatty acid accumulation triggers PARP1 hyperactivation and subsequent degradation, depleting RAD51 to compromise homologous recombination and induce parthanatos. These findings uncover a lipid-mediated vulnerability in GBM, linking fatty acid desaturation to PARP1-dependent genome integrity. Targeting SCD5 may offer a therapeutic strategy to eliminate therapy-resistant GSCs and enhance the efficacy of genotoxic or immunotherapeutic interventions.

Keywords:  CP: cancer; CP: metabolism; DNA repair; PARP1; cerebral organoids; fatty acid desaturation; glioma stem cells; lipid metabolism; parthanatos; stearoyl-CoA desaturase

DOI:  https://doi.org/10.1016/j.celrep.2026.117223
Cancer Res Commun. 2026 Apr 13.

ATR and PKMYT1 inhibition re-sensitize a subset of TNBC patient-derived models to carboplatin inducing mitotic catastrophe.

Juliet Guay, Hellen Kuasne, Catherine Chabot, Kathryn Bozek, Yasamin Majedi, Marguerite Buchanan, Adriana Aguilar-Mahecha, Eric Bareke, Benjamin Ulmer, Tim Kong, Kangning Yang, Minyan Liao, Oluwadara Elebute, Ruining Guo, Anie Monast, Geneviève Morin, Sidong Huang, Morag Park, Mark Basik.

Triple negative breast cancer (TNBC) is associated with poor prognosis and is mainly treated with chemotherapy-based regimens, often including carboplatin. Resistance to carboplatin is a common clinical issue that is either initially present or develops with treatment. Overcoming this resistance is a significant clinical challenge, which highlights the need for novel therapeutic strategies. We used a pooled shRNA screening approach with a chemoresistant TNBC patient-derived xenograft (PDX) cell (PDXC) line to identify targets whose knockdown would enhance the efficacy of carboplatin. This screening led to the identification of the ATR (ataxia telangiectasia and Rad3-related) gene as a key therapeutic vulnerability. Inhibiting ATR with BAY1895344 or AZD6738 re-sensitized carboplatin-resistant PDXCs and PDXs to carboplatin, resulting in an increase in DNA damage, and apoptosis. ATR inhibition prevents carboplatin-resistant cells from effectively engaging the S and G2/M checkpoints required for DNA repair, leading to mitotic catastrophe. We further identified that the addition of ATR inhibitors to carboplatin enabled FOXM1-targeted gene program leading to premature passage into mitosis. Moreover, targeting PKMYT1, a regulator of cyclin-dependent kinase 1 (CDK1) controlling the G2/M checkpoint, through knockdown or with the novel PKMYT1 inhibitor RP-6306, also enhanced carboplatin efficacy in our TNBC PDXC. Molecular factors associated with response to the ATR inhibitor/carboplatin combination included low RNA levels of PKMYT1. These results underscore the pivotal roles of ATR and PKMYT1 in mediating resistance to carboplatin in TNBC and support targeting these pathways to overcome carboplatin resistance in this disease.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0044
J Clin Invest. 2026 Apr 15. pii: e191735. [Epub ahead of print]136(8):

Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance.

Yikai Zhao, Yijia Zhou, Linnuo Pan, Geng G Tian, Hsin-Yi Huang, Shijie Tang, Ming Lu, Zhangsen Zhou, Peng Zhang, Luonan Chen, Lele Zhang, Liang Hu, Hongbin Ji.

  Complete response is rarely observed in lung cancer molecular targeted therapy, despite great clinical success. Here, we found that molecular therapy targeted toward EGFR mutant, KRAS mutant, or ALK fusion lung cancer induced cholesterol biosynthesis, which promoted cancer cells to enter dormancy and thus escape drug killing. Combined statin treatments effectively blocked cholesterol biosynthesis, prevented cancer cells from entering dormancy, and thus resulted in dramatic tumor regression. We further identified a subpopulation of cycling cancer cells that persisted during molecular targeted therapy and remained sensitive to aurora kinase inhibitors. Triple-targeting cholesterol biosynthesis, aurora kinase, and individual oncogenic drivers almost eradicated all the cancer cells. Therapy-induced cancer dormancy was mainly attributed to activation of unfolded protein response, specifically the PERK-eIF2α axis, which triggers cholesterol biosynthesis and AKT signaling. Collectively, this work uncovers an unexpected role of a therapy-induced prosurvival program in promoting cancer dormancy and provides a potentially effective strategy to prevent drug resistance.

Keywords:  Cancer; Cell biology; Drug therapy; Lung cancer; Metabolism

DOI:  https://doi.org/10.1172/JCI191735
bioRxiv. 2026 Apr 07. pii: 2026.04.03.716311. [Epub ahead of print]

SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.

Dingcheng Sun, Guangrui Ding, Haonan Lin, Guo Chen, Chun-Chin Wang, Seema Bachoo, Sarah E Bohndiek, Ji-Xin Cheng.

Mitochondria, acting as the energy powerhouse, biosynthetic center, and reductive equivalent hub of the cell, participate in cellular metabolic activities. However directly imaging mitochondrial chemical content and quantifying metabolic activity in living cells remain challenging. Here, by Self-PErmutation Noise2noise Denoiser enhanced Hyperspectral Stimulated Raman Scattering (SPEND-hSRS) microscopy, we demonstrate fingerprint-region metabolic imaging of fumarate, a key intermediate in the tricarboxylic acid (TCA) cycle, with sub-millimolar sensitivity. In chemotherapy-stressed bladder cancer cells, fumarate imaging revealed two mitochondrial subpopulations with divergent TCA metabolic preferences quantified by ratio metric analysis. Pixel-wise least absolute shrinkage and selection operator (LASSO) spectral unmixing further reconstructs fumarate and lipid maps, uncovering localized fumarate enrichment in protrusions. Extending to CH-window hyperspectral SRS imaging, we uncover the interplay between mitochondria and lipid droplets (LDs) in protrusions, where fatty acid is found to be released from LDs, to fuel the TCA cycle. Together, our work establishes SPEND-hSRS as high-resolution platform for linking fumarate to mitochondrial heterogeneity. Our results provide new insights into how mitochondrial heterogeneity and interaction with LDs drive cancer cell adaptation to stress.

DOI: https://doi.org/10.64898/2026.04.03.716311
Oncogene. 2026 Apr 13.

Dual inhibition of glycolysis and glutaminolysis by targeting FOXO3 for hepatocellular carcinoma treatment.

Fan Wang, Meng Huang, Kaixuan Sheng, Yue Yan, Beibei Zhang, Xinlei Wang, Zhiyi Yang, Mengyi Li, Yuping Liu, Qi Qi, Yuejun Sun, Chenglin Li.

Metabolic reprogramming is a hallmark of tumorigenesis and progression in hepatocellular carcinoma (HCC) and has emerged as a promising therapeutic strategy. Forkhead box O3 (FOXO3), a critical nuclear transcription factor, is dysregulated in multiple cancers; however, its precise role in HCC progression remains unclear. In this study, we demonstrate that enhanced glycolysis and glutaminolysis are pivotal metabolic features of HCC, with tumor cells heavily relying on both pathways for survival and proliferation. We identify FOXO3 as a tumor suppressor in HCC that inhibits key metabolic enzymes and metabolites involved in these pathways. This inhibitory effect is mediated through suppression of yes-associated protein (YAP). Mechanistically, FOXO3 directly binds to the GTGAACAT motif (-1824 to -1817) within the YAP promoter, leading to transcription repression of YAP and subsequent disruption of YAP-driven metabolic programs. Pharmacological activation of FOXO3 using specific inducers markedly reduced YAP expression, resulting in inhibition of glycolysis, glutaminolysis, and proliferation in HCC cells. In vivo, activation of the FOXO3/YAP axis effectively suppressed HCC progression through the coordinated inhibition of glycolysis and glutaminolysis. Moreover, FOXO3 inducers significantly impaired the growth and viability of patient-derived HCC organoid models. Hence, these findings identify FOXO3 as a key regulator of metabolic reprogramming in HCC and establish the FOXO3/YAP axis as a promising therapeutic target, suggesting potential strategies for metabolic-based interventions in HCC treatment.

DOI: https://doi.org/10.1038/s41388-026-03765-1
J Adv Res. 2026 Apr 14. pii: S2090-1232(26)00342-5. [Epub ahead of print]

Peroxisome-derived and liver-specific hydroxyacid oxidase 1-mediated hydrogen peroxide promotes ferroptosis by augmenting peroxisomal ROS.

Xintong Peng, Yanling Zhou, Jielin Chen, Zuli Wang, Xin Peng, Haiyan Wang, Long Shu, Na Liu, Yao Long, Li Linghu, Zewen Zhang, Yuanhao Peng, Yuzheng Zhao, Desheng Xiao, Ying Shi, Shuang Liu, Yongguang Tao.

   INTRODUCTION: While peroxisome-associated molecules have been implicated in ferroptosis, the mechanistic relationship between peroxisomes and ferroptosis remains poorly understood. Key unresolved questions include whether peroxisomal hydrogen peroxide (H2O2)-generating enzymes, such as hydroxyacid oxidase 1 (HAO1), contribute to ferroptosis, as well as how they function at the molecular level.
OBJECTIVES: This study was designed to investigate the role of HAO1-mediated peroxisomal H2O2 production in ferroptosis and its impact on liver cancer progression.
METHODS: We evaluated HAO1 expression in liver cancer and its association with patient prognosis using clinical samples and bioinformatic analyses. RNA sequencing was performed to identify HAO1-regulated biological pathways. Cell viability was measured with a CCK-8 assay, and ferroptosis was assessed using a C11-BODIPY 581/591 probe, iron assay, and GSH detection. To delineate how HAO1-induced alterations in peroxisomal H2O2 affect ferroptosis, we employed the H2O2-specific HyPer probe in conjunction with immunofluorescence and flow cytometry. The role of HAO1 in malignant progression was further examined through in vitro and in vivo functional experiments.
RESULTS: HAO1 was found to enhance lipid peroxidation in liver cancer cells by boosting ROS levels within peroxisomes in an enzyme activity-dependent manner. Furthermore, HAO1 downregulated the p-STAT3/SLC7A11/GPX4 pathway, disrupting glutathione synthesis and impeding ROS scavenging, thereby heightening the susceptibility of cancer cells to ferroptosis. Through this dual mechanism, HAO1 synergistically promoted lipid peroxidation, triggering ferroptosis and inhibiting liver cancer cell proliferation and metastasis. Moreover, coenzyme Flavin Mononucleotide (FMN) was shown to augment the tumor-suppressive activity of HAO1.
CONCLUSION: Our findings shed light on the key role of HAO1 in the peroxisome-mediated redox regulation of ferroptosis during liver cancer progression, providing a potential target for liver cancer treatment.

Keywords:  Abscisic acid; Entomopathogens; Glycine max; Plant growth promotion; RNA-Seq; Stomata

DOI:  https://doi.org/10.1016/j.jare.2026.04.038
Int J Mol Sci. 2026 Mar 27. pii: 3065. [Epub ahead of print]27(7):

Identification of a Prognostic Gene Signature for Chemoresistance Prediction in Lung Adenocarcinoma by Screening Mitochondrial Metabolism Gene Sets.

Binbin Tan, Jinxu Yang, Xibao Zhao, Shanshan Liu.

  Chemoresistance is a major challenge in lung adenocarcinoma (LUAD) treatment and is associated with mitochondrial metabolism. Using publicly available LUAD transcriptome data, we established a five-gene prognostic signature (YWHAZ, HSPD1, NOTCH3, PGK1, and PPARG) for LUAD through differential gene expression profiling, univariate Cox analysis, and machine learning-based feature selection. Patients with LUAD were classified into a high-risk group (HRG) and a low-risk group (LRG) based on their risk scores. Enrichment analysis revealed significant differences between the HRG and LRG in multiple pathways related to metabolism and immunity. The immune microenvironment also differed significantly between the two groups, and the prognostic genes were correlated with infiltrating immune cells. A total of 110 compounds exhibited differential sensitivity across the groups. Molecular docking demonstrated a favorable binding affinity between the prognostic genes and the predicted drugs. Furthermore, YWHAZ knockdown significantly suppressed cancer cell proliferation in cell and animal models. In addition, YWHAZ knockdown markedly reduced cisplatin resistance by downregulating key regulators of the DNA replication and repair pathway, including POLA1 and MCM4. These results provide insight into the molecular mechanisms underlying chemoresistance and identify putative therapeutic targets for LUAD treatment.

Keywords:  chemoresistance; lung adenocarcinoma; mitochondrial metabolism; molecular docking

DOI:  https://doi.org/10.3390/ijms27073065
Clin Cancer Res. 2026 Apr 17.

Lactate-induced lactylation enhances BMAL1 transcription and nuclear translocation, promoting bevacizumab resistance in glioblastoma through VEGFA.

Fan Wang, Wenjun Liao, Caiyan Li, Rui Duan, Lvan Chen.

PURPOSE: Resistance to bevacizumab (Bev) remains a major challenge in the management of glioblastoma multiforme (GBM). Our previous work indicated that BMAL1 participates in lactate metabolism in GBM and may be involved in the mechanisms underlying Bev resistance. However, the specific roles of BMAL1 and lactate in this process require further investigation.
EXPERIMENTAL DESIGN: This study employed a comprehensive strategy combining in vitro GBM cell line models, patient-derived xenografts (PDX), and in vivo mouse studies. Functional assays (CCK-8, 3D spheroid invasion), molecular techniques (ChIP-qPCR, Co-IP, IP-MS), and biochemical analyses were performed to dissect the mechanism. The clinical relevance of our findings was validated in five independent GBM cohorts and through analysis of human GBM tissues.
RESULTS: We identified a previously unrecognized signaling axis in which lactate promotes BMAL1 expression via H3K18la modification at its promoter. In addition, lactate induces BMAL1 protein lactylation at lysine 123, which facilitates its nuclear translocation. IP-MS further showed that lactylated BMAL1 displays a strengthened interaction with TUBA1C, a protein essential for its nuclear import. This lactylation-dependent BMAL1/TUBA1C complex subsequently enhances VEGFA transcription, thereby driving Bev resistance. Importantly, targeting this pathway either by silencing BMAL1, inhibiting lactate transporters, or introducing a lactylation-deficient BMAL1-K123 mutant effectively restored Bev sensitivity in vitro and in vivo.
CONCLUSIONS: These findings reveal a novel mechanism through which lactate-mediated lactylation of BMAL1 promotes Bev resistance in GBM, supporting the lactate/BMAL1/TUBA1C/VEGFA axis as a promising therapeutic target for overcoming Bev resistance in GBM patients.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-2352