bims-meract 2026-05-03 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–05–03
eighteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

GLUL drives metabolic reprogramming and confers docetaxel resistance in prostate cancer.
KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.
ENO1 promotes acute myeloid leukemia progression through SCD1-mediated lipid metabolism reprogramming.
GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer.
BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma.
Metabolic regulation of histone acetylation by ACLY supports MDR1 expression in colorectal cancer and highlights a targetable vulnerability.
SEPHS2 loss reprograms cancer metabolism from oxidative phosphorylation to gluconeogenesis via PCK1 stabilization.
LITAF suppresses breast cancer and paclitaxel resistance by ubiquitinating and degrading PCMT1 to inhibit COX-2-dependent arachidonic acid metabolism.
Locoregional lactate dehydrogenase inhibition potentiates therapy and overcomes treatment resistance in hepatocellular carcinoma.
The ATF4/PSAT1/JNK Signaling Axis Suppresses Ferroptosis to Drive Venetoclax Resistance in AML.
Reprogramming lipid metabolism in pediatric cancers.
Mitochondrial double-stranded RNA fuels pancreatic cancer growth via RIG-I/TLR3 inflammation.
Crosstalk between integrin signaling and NAD⁺ biosynthetic pathways promotes glycolysis, proliferation, survival, and tumor growth in triple-negative breast cancer.
Cyclin-dependent kinase-9 and oxidative phosphorylation inhibition overcome ibrutinib resistance in mantle cell lymphoma.
LIPT1 loss confers replication stress and PARP inhibitor sensitivity through PrimPol-mediated ssDNA gaps.
Cancer cell-intrinsic SSBP4 enables tumor immune evasion by promoting cholesterol biosynthesis.
Tim-3 facilitates dendritic cell ferroptosis and impairs anti-tumor immunity in steatohepatitis-related HCC.
Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas.

Biochem Pharmacol. 2026 Apr 25. pii: S0006-2952(26)00341-2. [Epub ahead of print]250(Pt 2): 118008

GLUL drives metabolic reprogramming and confers docetaxel resistance in prostate cancer.

Zihang Wu, Yuqi Wu, Qiuxia Ding, Wei Huang, Yuanfei Huang, Ying Zhang, Ran Xu, Xiangwei Wang.

  Docetaxel is a first-line chemotherapeutic agent for advanced and castration-resistant prostate cancer (CRPC), yet acquired resistance limits its long-term efficacy. Metabolic reprogramming has emerged as a central mechanism of therapeutic resistance; however, the metabolic determinants of docetaxel resistance remain incompletely defined. Here, we identify glutamate-ammonia ligase (GLUL), the key enzyme mediating de novo glutamine synthesis, as a critical regulator of docetaxel resistance. Integrated transcriptomic, metabolomic, and single-cell RNA sequencing analyses of clinical specimens revealed significant enrichment of amino acid metabolic pathways, with glutamine metabolism as a dominant alteration. GLUL was consistently upregulated in resistant tumors and validated across independent cohorts. High GLUL expression was associated with activation of PI3K-AKT-mTOR signaling, glycolysis, and oxidative phosphorylation. Functionally, GLUL overexpression enhanced glutamine metabolic flux, promoted cell cycle progression, suppressed docetaxel-induced apoptosis, and increased cell viability under treatment. Conversely, GLUL knockdown restored chemosensitivity in resistant cells and significantly suppressed tumor growth in xenograft models. Mechanistically, GLUL-driven metabolic reprogramming reshaped bioenergetic and redox homeostasis and was tightly coupled to pro-survival signaling activation, forming a coordinated metabolism-signaling network that supports chemoresistance. Collectively, these findings establish GLUL as a key metabolic driver of docetaxel resistance and highlight glutamine synthesis as a pharmacologically actionable vulnerability in CRPC.

Keywords:  Chemoresistance; Docetaxel; GLUL; Glutamine; Prostate cancer

DOI:  https://doi.org/10.1016/j.bcp.2026.118008
Cancer Res. 2026 Apr 29.

KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.

Ravi Thakur, Dezhen Wang, Tuo Hu, Chunbo He, Junzhang Zhao, Voddu Suresh, Girish H Rajacharya, Anjan K Pradhan, Vira Chumak, Carlos A Valenzuela, Asha D Kushwaha, Drew A Labreck, Tae Gyu Oh, Kar-Ming Fung, Daniel Zhao, Naoko Takebe, Susanna V Ulahannan, Surendra K Shukla, Kirsten L Bryant, Channing J Der, Kamiya Mehla, Pankaj K Singh.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations, which activate the MAPK pathway to promote PDAC progression. Here, we explored metabolic vulnerabilities of PDAC by assessing initial metabolic reprogramming upon ERK inhibition using metabolomics, lipidomics, and isotope-tracing experiments. ERK inhibition enhanced lipid turnover and fatty acid oxidation while inhibiting glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Moreover, lipophagy, but not cytosolic lipolysis, was responsible for the increased lipid turnover and fatty acid oxidation upon ERK inhibition. Lipophagy and lipophagy-fueled fatty acid oxidation were induced by increased nuclear translocation and activity of the transcription factor TFEB. Pharmacological inhibition of fatty acid oxidation in combination with KRASG12D/MEK/ERK inhibitors synergistically decreased the growth of PDAC cell lines and organoids. The combination decreased tumor burden and improved survival in orthotopic cell line and patient-derived xenograft PDAC models. Overall, this study provides mechanistic insights into the development of metabolic resistance to KRAS signaling inhibition and demonstrates that fatty acid oxidation is a metabolic vulnerability following KRAS signaling inhibition that can be utilized as an effective therapeutic target to treat PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1984
Blood Adv. 2026 Apr 28. pii: bloodadvances.2025017973. [Epub ahead of print]

ENO1 promotes acute myeloid leukemia progression through SCD1-mediated lipid metabolism reprogramming.

Yijun Wu, Li Gao, Fang Fang, Zhiheng Li, Yixin Hu, Yongping Zhang, Chenwei Yang, Zhongling Wei, Xin Liu, Ying Yang, Fenli Zhang, Weiliang Zhang, Kaixuan Sun, Yizhen Li, Chun Yang, Jian Pan, Shaoyan Hu.

Alpha-enolase (ENO1) is a potential therapeutic target in acute myeloid leukemia (AML) owning to its elevated expression in AML cells. In this study, we investigated the association between high ENO1 expression, accelerated tumor progression and poor AML prognosis. Transcriptomic and metabolomic analyses indicated that ENO1 directly modulates lipid metabolism via regulating Stearoyl-CoA Desaturase 1 (SCD1) expression. We further demonstrated that ENO1 functions as a DNA-binding protein, interacting with the SCD1 promoter region to enhance SCD1 transcription. This results in increased synthesis of monounsaturated fatty acids, leading to increased resistance to lipid peroxidation and ferroptosis. Based on these results, we found that SSI-4, an SCD1 inhibitor, could enhance chemosensitivity of daunorubicin (DNR), which can induce ferroptosis in tumor cells, effectively reduced the resistance to ferroptosis in AML cells exhibiting high ENO1 expression. Overall, our study elucidates the mechanism of ENO1 promotes SCD1 transcription, driving lipid reprogramming and ferroptosis resistance within AML. Additionally, it highlights the therapeutic potential of combining SCD1 inhibition with DNR for AML patients with elevated ENO1 expression levels.

DOI: https://doi.org/10.1182/bloodadvances.2025017973
Clin Epigenetics. 2026 Apr 29. pii: 76. [Epub ahead of print]18(1):

GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer.

Janina Müller, Emre Sofyali, Luisa Schwarzmüller, Yael Aylon, Eviatar Weizman, Lisa Schlicker, Katherine Kelly, Simone Borgoni, Simin Oz, Cole Stocker, Sara Burmester, Angelika Wörner, Sabine Karolus, Birgitta E Michels, Daniela Heiss, Rainer Will, Veronica Rodrigues de Melo Costa, Pavlo Lutsik, Dieter Weichenhan, Ilse Hofmann, Nishanth Belugali Nataraj, Yosef Yarden, Luca Magnani, Christoph Plass, Almut Schulze, Cindy Körner, Moshe Oren, Stefan Wiemann.

   BACKGROUND: Estrogen receptor alpha (ERα)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success.
RESULTS: We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses these effects and reduces proliferation under estrogen-deprived conditions. Notably, GLYATL1 expression is positively regulated by estrogen receptor alpha signaling, however, independently of estrogen.
CONCLUSIONS: These findings reveal GLYATL1 as a metabolic and epigenetic mediator of endocrine therapy resistance, suggesting it as a potential target to overcome AI resistance in luminal breast cancer.

Keywords:  Aromatase inhibition; Endocrine therapy resistance; Estrogen-receptor alpha (ERα); GLYATL1; Luminal breast cancer

DOI:  https://doi.org/10.1186/s13148-026-02133-w
Cell Rep Med. 2026 Apr 29. pii: S2666-3791(26)00201-6. [Epub ahead of print] 102784

BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma.

Misty Shuo Zhang, Kenneth Kin-Leung Kwan, Aki Pui-Wah Tse, Gengchao Wang, Larry Lai Wei, Kejie Sun, Noreen Nog-Qin Chui, Derek Lee, Macus Hao-Ran Bao, Xiaoxuan Pang, Zhenqi Wu, Yanyan Chen, Yangyang Wang, Zifan Yang, Xue Jiang, Qidong Li, Yan Zhang, Yajie Zhong, Jacinth Wing-Sum Cheu, Yiling Chen, Weixing Li, Chun-Ming Wong, Jianing Wang, Zongwei Cai, Qi Zhang, Tingbo Liang, Irene Oi-Lin Ng, Adonia E Papathanassiu, Carmen Chak-Lui Wong.

  Hypoxia is a common characteristic of solid tumors, especially in hepatocellular carcinoma (HCC). Hypoxia-inducible factors (HIFs), particularly HIF-1α, mediate metabolic adaptation, which is crucial for survival of hypoxic cells. Branched-chain amino transferase 1 (BCAT1) catalyzes the reversible transamination reaction between branched-chain amino acids (BCAAs) and branched-chain keto acids (BCKAs), involving the inter-conversion of α-ketoglutarate (α-KG) and glutamate. We investigate and delineate the mechanisms by which BCAT1 consumes α-KG and stabilizes HIF-1α, suppressing α-KG-dependent oxygen dehydrogenase, prolyl hydroxylase-domain protein (PHD), inducing HIF-1α-mediated metabolic reprogramming and promoting hypoxic survival of HCC. We evaluate the potency of a BCAT1 inhibitor, ERG245, as a single or combination treatment with tyrosine kinase inhibitor (TKI) in vivo. We further validate the over-expression and correlation of BCAT1 and HIF-1α downstream metabolic genes in HCC clinical samples. Our results indicate that BCAT1 benefits HCC growth through HIF-1α-induced metabolic reprogramming. Targeting BCAT1 will provide an effective therapeutic strategy for HCC patients.

Keywords:  EGR245; branched-chain amino transferase 1; hepatocellular carcinoma; hypoxia; hypoxia-inducible factor; metabolic reprogramming; prolyl hydroxylase-domain protein; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.xcrm.2026.102784
Neoplasia. 2026 Apr 30. pii: S1476-5586(26)00044-8. [Epub ahead of print]77 101314

Metabolic regulation of histone acetylation by ACLY supports MDR1 expression in colorectal cancer and highlights a targetable vulnerability.

Ana García-Bautista, Aiora Cenigaonandia-Campillo, Anxo Rio-Vilariño, Lara Sanz-Criado, Marta Selva-Giménez, Raquel Perez-Antolín, Arancha Cebrián, Laura García-García, María Jesús Fernández-Aceñero, Natalia Baños-Herraiz, Lorena Mozas-Vivar, Estrella Núñez-Delicado, Jesús García-Foncillas, Óscar Aguilera.

  Chemoresistance remains a major cause of treatment failure in colorectal cancer (CRC), yet the metabolic mechanisms sustaining efflux-mediated drug resistance are not fully defined. Here, we identify ATP-citrate lyase (ACLY) as a metabolic regulator linking citrate-dependent acetyl-CoA production to epigenetic control of MDR1/ABCB1 expression. Using genetic and pharmacologic approaches, we show that ACLY catalytic activity contributes to the maintenance of histone acetylation at H3K9 and H4K16 and supports MDR1 transcription in CRC cells. Consistently, ACLY overexpression enhances, whereas its inhibition reduces, MDR1 expression and associated resistance-related transcriptional programs. In human CRC specimens, ACLY and MDR1 levels positively correlate, with a stronger association observed in advanced-stage tumors, supporting clinical relevance of this metabolic-epigenetic axis. Metabolic tracing with 13C-glucose suggests that perturbation of citrate flux influences ACLY-associated pathways and acetyl-CoA availability. In this context, vitamin C treatment reduces citrate-derived acetyl-CoA and ACLY phosphorylation and is associated with global histone deacetylation and decreased MDR1 expression in vitro and in KRAS-mutant patient-derived xenografts. Together, these findings highlight ACLY-dependent acetyl-CoA production as a potential metabolic vulnerability linked to epigenetic regulation of drug efflux programs in CRC. Targeting this metabolic-chromatin axis may represent a strategy to modulate MDR1-associated chemoresistance.

Keywords:  ACLY; Ascorbate; Cancer; Chemoresistance; Epigenetic; KRAS; MDR-1; Metabolism

DOI:  https://doi.org/10.1016/j.neo.2026.101314
Cell Rep. 2026 Apr 25. pii: S2211-1247(26)00375-X. [Epub ahead of print]45(5): 117297

SEPHS2 loss reprograms cancer metabolism from oxidative phosphorylation to gluconeogenesis via PCK1 stabilization.

Yihuizhi Zhang, Qinghua Zhang, Bi Wei, Wenzhou Wang, Xinyu Chen, Weijian Ding, Chenguang Li, Yirui Ye, Jiali Xu, Weibo Zhang, Linyue Li, Fengyi Mai, Wenyou He, Xiancai Du, Keyu Zhao, Zining Zhao, Jingnan Huang, Yuchun Niu, Yue Zhang, Lingyun Dai, Baotong Zhang, Siyuan Xia.

  Selenium maintains cellular redox homeostasis primarily through its incorporation into selenoproteins. However, whether and how selenium metabolism modulates oxidative phosphorylation (OXPHOS), a major endogenous source of oxidative stress, has remained unclear. Here, we performed an OXPHOS-focused screen targeting selenium-metabolizing enzymes and identified SEPHS2 as a central hub linking selenium metabolism to OXPHOS. SEPHS2 knockout suppresses OXPHOS while retaining glucose as the primary carbon source of cellular respiration and redirecting glucose metabolism toward gluconeogenesis and the downstream pentose phosphate pathway (PPP). Mechanistically, SEPHS2 loss elevates intracellular NAD+ levels, thereby activating the deacetylase SIRT2 as a cofactor and promoting deacetylation-dependent stabilization of the gluconeogenic enzyme PCK1. Under selenium-limited conditions, SEPHS2 is reduced. SEPHS2 loss promotes tumor spread to the lung and sensitizes tumors to the PPP inhibitor 6-aminonicotinamide. These findings define a selenoprotein biosynthesis-independent role of SEPHS2 in regulating OXPHOS and unveil the PPP as a therapeutic vulnerability in tumors adapting to a selenium-limited microenvironment.

Keywords:  CP: cancer; CP: metabolism; OXPHOS; PCK1; SEPHS2; cancer metabolism; gluconeogenesis; pentose phosphate pathway; selenium metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.117297
Front Pharmacol. 2026 ;17 1706420

LITAF suppresses breast cancer and paclitaxel resistance by ubiquitinating and degrading PCMT1 to inhibit COX-2-dependent arachidonic acid metabolism.

Na Yang, Jingying Cao, Feng Jiang, Renxian Cao, Yiqi Liu.

   Background: Paclitaxel (PTX) is a first-line chemotherapeutic agent extensively employed in the management of breast cancer (BC); however, the emergence of drug resistance frequently results in unsatisfactory clinical outcomes and poor prognosis. This study aimed to investigate the pathogenic mechanisms that drive PTX resistance in BC.
Methods: Tumor and matched adjacent normal tissues were collected from 30 BC patients treated with PTX. Untargeted metabolomics was performed to analyze the metabolic differences. The expression of lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF), protein L-isoaspartyl (D-aspartyl) methyltransferase (PCMT1), and cyclooxygenase-2 (COX-2) was assessed using RT-qPCR, immunoblotting, and immunohistochemistry (IHC). Cell proliferation was determined via CCK-8 and colony formation assays, cell apoptosis was analyzed by flow cytometry, and enzyme-linked immunosorbent assay (ELISA) was used to measure arachidonic acid (AA) and prostaglandin E2 levels. The interaction between LITAF and PCMT1, as well as the ubiquitination level of PCMT1, was investigated using co-immunoprecipitation (Co-IP). In vivo, nude mice were used to explore the effect of LITAF on tumor response to PTX treatment.
Results: PCMT1 and COX-2 were upregulated in BC tissues, particularly in PTX-resistant patients, whereas LITAF expression was downregulated. In BC tissues, LITAF expression was negatively correlated with PCMT1 levels, while PCMT1 expression showed a positive correlation with COX-2 levels. PCMT1 knockdown attenuated COX-2-mediated AA metabolism, suppressed BC cell proliferation, and increased the sensitivity of BC cells to PTX. LITAF interacted with PCMT1 and promoted ubiquitination-mediated degradation of PCMT1, thereby inhibiting COX-2-mediated AA metabolism, reducing the proliferation of PTX-resistant BC cells, and enhancing the sensitivity of BC cells to PTX in vivo.
Conclusion: LITAF regulates the ubiquitination-mediated degradation of PCMT1 to inhibit COX-2-dependent AA metabolism, thereby enhancing the sensitivity of BC cells to PTX and providing a potential therapeutic strategy to overcome PTX resistance in BC.

Keywords:  AA metabolism; LITAF; PCMT1; PTX-resistance; breast cancer

DOI:  https://doi.org/10.3389/fphar.2026.1706420
Hepatology. 2026 Apr 30.

Locoregional lactate dehydrogenase inhibition potentiates therapy and overcomes treatment resistance in hepatocellular carcinoma.

Daniel J Boehmler, Ryan J Baron, Jennifer A Brain, Ariful Islam, Yohan Kim, Alexey Gurevich, Nicholas R Perkons, Alexander I Zavriyev, Rudra Amin, Jessica Andrew-Udoh, Erena Tuzneen Supan, Ryan El Ghazal, Stephen J Hunt, George McClung, David Tischfield, Daniel Ackerman, Aalim M Weljie, Kelley Weinfurtner, Nicolas Skuli, Terence P Gade.

   BACKGROUND AIMS: Metabolic inhibitors have demonstrated limited efficacy for cancer therapy due to metabolic plasticity and systemic toxicity. Locoregional therapies (LRT), such as transarterial embolization (TAE) or transarterial chemoembolization (TACE), generate ischemic stress that reprograms the tumor microenvironment (TME) toward glycolytic dependency, creating an opportunity to sensitize hepatocellular carcinoma (HCC) to metabolic inhibition. This study investigated whether pharmacologic inhibition of lactate dehydrogenase (LDH) with NCATS-SM1441 could exploit TAE-induced metabolic vulnerabilities to improve therapeutic efficacy in HCC.
APPROACH RESULTS: Human HCC cell lines were exposed to replete or ischemic (TAE-like) conditions and treated with the LDH inhibitor NCATS-SM1441. Glucose/lactate flux, adenosine triphosphate (ATP) levels, and viability were assessed. In vivo, a diethylnitrosamine (DEN)-induced rat HCC model was treated with intraarterial NCATS-SM1441, TAE, or their combination. Drug distribution, tumor metabolism, necrosis, and survival were analyzed using mass spectrometry imaging, histopathology, T2-weighted magnetic resonance imaging (MRI), and survival metrics. Ischemic conditions induced LDHA expression and glycolytic flux, enhancing susceptibility to LDH inhibition. The combination of intraarterial NCATS-SM1441 before embolization increased intratumoral drug accumulation, reduced systemic exposure, and synergized with TAE to suppress lactate production, promote tumor necrosis, and significantly extend local progression-free survival.
CONCLUSIONS: TAE conditions the TME to create a therapeutically targetable glycolytic dependency. Combining TAE with LDH inhibition overcomes key limitations of metabolic inhibitors as monotherapies, enhancing local control and survival with minimal systemic toxicity, supporting integration of metabolism-targeted agents with LRT for unresectable HCC.

Keywords:  Liver cancer; TACE; cancer cell metabolism; hepatocellular carcinoma; lactate dehydrogenase; locoregional therapy; metabolic inhibition

DOI:  https://doi.org/10.1097/HEP.0000000000001775
Exp Cell Res. 2026 Apr 25. pii: S0014-4827(26)00162-X. [Epub ahead of print] 115045

The ATF4/PSAT1/JNK Signaling Axis Suppresses Ferroptosis to Drive Venetoclax Resistance in AML.

XunXun Zhu, WenHui Huang, MingYan Zhang, YanLing Tao, Hao Zhang.

  Metabolic reprogramming has emerged as a key driver of therapy resistance in acute myeloid leukemia (AML). Here, we identify phosphoserine aminotransferase 1 (PSAT1) as a critical metabolic determinant of venetoclax (VEN) resistance through the suppression of ferroptosis. PSAT1 was consistently upregulated in VEN-resistant cell lines and relapsed patient samples. Mechanistically, the transcription factor ATF4 directly bound the PSAT1 promoter, enhancing its expression and subsequently promoting glutathione synthesis, depleting the labile iron pool, and attenuating lipid peroxidation. Concurrently, PSAT1 functioned to restrain JNK/c-Jun signaling. Knockdown of PSAT1 restored VEN sensitivity by triggering ferroptosis and modulating the expression of BCL-2 and GPX4. Clinically, elevated PSAT1 expression predicted poor patient survival. Our findings unveil the ATF4/PSAT1/JNK axis as a master regulator of ferroptosis in AML, revealing a druggable pathway to overcome VEN resistance.

Keywords:  ATF4; Acute myeloid leukemia; JNK/c-Jun signaling; PSAT1; ferroptosis; venetoclax resistance

DOI:  https://doi.org/10.1016/j.yexcr.2026.115045
Oncogenesis. 2026 Apr 30.

Reprogramming lipid metabolism in pediatric cancers.

Vinzent L Lindemann, Nazek Noureddine, Raphael J Morscher.

Metabolic reprogramming is a defining feature of malignant transformation and cancer cell growth. Pediatric cancers arise from genetic disruptions hijacking developmental programs by aberrant transcriptional networks. This coordinated rewiring shapes lipid metabolism through activation of biosynthetic pathways, membrane remodeling, and metabolic flexibility. This review synthesizes recent advances in the understanding of lipid metabolism reprogramming across pediatric cancers, examining four key areas: (1) transcriptional drivers that activate fatty acid and cholesterol synthesis; (2) lipid catabolism sustaining ATP, acetyl-CoA and NADPH pools under metabolic stress; (3) ferroptosis evasion through desaturation pathways and membrane remodeling; and (4) tissue-specific metabolic adaptations enabling metastasis to the bone marrow and cerebrospinal fluid. Despite extensive preclinical evidence identifying targetable vulnerabilities - including dependencies on FASN, SCD, and HMGCR - clinical impact remains to be proven. We discuss challenges of introducing therapies targeting lipid metabolism to the clinic and argue that the future lies in a better understanding of lipid flux and patient-specific dependencies.

DOI: https://doi.org/10.1038/s41389-026-00617-1
Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2528281123

Mitochondrial double-stranded RNA fuels pancreatic cancer growth via RIG-I/TLR3 inflammation.

Andrew T Milcarek, Minjeong Yeon, Camilla Esposito, Prerna Kulkarni, Andrew V Kossenkov, Jozef Madzo, Anneliese M Faustino, Hsin-Yao Tang, Alessandra M Storaci, Alessandro Palleschi, Marco Locatelli, Valentina Vaira, Mary V Iacocca, Andrea Ward, Arvind Sabesan, Nicholas J Petrelli, Michela Perego, Dario C Altieri.

  Mitochondria activate inflammation and innate immunity to protect against infections, but the role in cancer is unknown. Here, we report that patients with pancreatic ductal adenocarcinoma (PDAC) with reduced levels of the mitochondrial scaffold, Mic60, or inner mitochondrial membrane protein, exhibit increased inflammation, high NFκB activity and production of TNFα. This is mediated by double-stranded RNA (dsRNA) released from structurally defective, Mic60-low mitochondria, which engages TLR3/RIG-I sensing, activates NFκB gene expression and reprograms transcriptional and signaling networks to promote PDAC proliferation. Preclinical targeting of mitochondrial dsRNA signaling triggers rapid cell death and inhibition of tumor growth, selectively in Mic60-knockdown PDAC, without overt toxicity, in vivo. Therefore, dsRNA released from defective mitochondria generates protumorigenic inflammation and provides an actionable therapeutic target in selected PDAC patients.

Keywords:  TLR3; dsRNA; inflammation; pancreatic cancer; viral mimicry

DOI:  https://doi.org/10.1073/pnas.2528281123
Oncogene. 2026 Apr 29.

Crosstalk between integrin signaling and NAD⁺ biosynthetic pathways promotes glycolysis, proliferation, survival, and tumor growth in triple-negative breast cancer.

Orion Spellecy, Javeria Qadir, Rongbo Han, Kai Zhu, Bingwei Xu, Yang Zhang, Isha Aryal, Ruei-Lung Lin, An-Hsuan Lin, Abu Saleh Mosa Faisal, Dana Napier, Dava Piecoro, Tim Scott, Penghui Lin, Li Chen, Lawrence D Brewer, Chi Wang, Natasha Kyprianou, Zhenheng Guo, Ruihua Guo, Olivier Thibault, Burton B Yang, Xiuwei H Yang.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Here, we investigated how integrin-dependent signaling pathways regulate tumor metabolism and therapeutic vulnerability in TNBC. Pharmacological inhibition of the integrin/FAK axis and/or BRD4 induced cell cycle arrest, autophagy, and senescence in highly proliferative cells, consistent with a metabolic stress phenotype. Metabolomic analyses using [U-¹³C]-glucose revealed a marked suppression of glycolytic carbon flux, accompanied by an approximately 30-47% reduction in intracellular NAD⁺ levels and coordinated alterations in NADH and tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate. Mechanistically, we identified nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD⁺ biosynthesis, as a central metabolic node integrating signaling/function of the two axes. NAMPT expression/activity was sustained transcriptionally or post-translationally, including sirtuin-associated deacetylation and neddylation-dependent proteasomal turnover. In BRCA1/2-deficient TNBC, integrin-FAK and NAMPT/NAD+ pathways converged on Wnt/β-catenin signaling to regulate DNA repair, and response to PARP1/2 inhibitors. Co-inhibiting FAK and NAMPT synergistically suppressed tumor growth by approximately 80%. Elevated stromal NAMPT expression was associated with a trend toward favorable clinical outcomes. Collectively, these findings uncover a previously unrecognized crosstalk between integrin/FAK and NAMPT/NAD⁺ pathways in TNBC and identify a synthetic lethal-like therapeutic vulnerability that warrants further evaluation in clinically relevant models.

DOI: https://doi.org/10.1038/s41388-026-03780-2
Cancer Res Commun. 2026 Apr 28.

Cyclin-dependent kinase-9 and oxidative phosphorylation inhibition overcome ibrutinib resistance in mantle cell lymphoma.

Carly Roleder, Xiaofan Zhao, Vi Lam, Haifeng Shen, Edward C Dominguez, Canping Chen, Sonia Rodriguez-Rodriguez, Lili Wang, Tycel Phillips, Zheng Xia, Alexey V Danilov.

Resistance to Bruton tyrosine kinase inhibitors (BTKi) is inevitable in mantle cell lymphoma (MCL). Cyclin-dependent kinase-9 (CDK9), a key regulator of oncogenic transcription, is a promising therapeutic target. Here we studied a selective CDK9 inhibitor, AZD4573, in MCL. Treatment with AZD4573 thwarted growth of both parental and ibrutinib-resistant MCL cell lines and primary MCL cells and downregulated expression of MYC and MCL1. However, CDK9 inhibition enhanced basal and maximal oxygen consumption rate, as well as increased production of ATP and reactive oxygen species in ibrutinib-resistant cell lines and primary MCL cells. While treatment with AZD4573 led to modest prolongation of survival in an ibrutinib-resistant MCL PDX mouse model, accompanied by downregulation of TNF/NF-B and mTORC1 signaling pathways in murine splenocytes, OxPhos was upregulated suggesting tumor metabolic reprogramming. Single-cell RNA Sequencing analysis of PBMCs from patients treated with AZD4573 on a clinical trial demonstrated sustained downregulation of MYC targets and OxPhos in malignant B-cells from a responding patient with MCL. Conversely, two refractory patients exhibited upregulation of MYC targets and OxPhos in PBMCs. OxPhos inhibitor IACS-010759 demonstrated synergy with AZD4573 in vitro. Thus, CDK9 inhibition exhibits activity in ibrutinib-resistant MCL and can be further enhanced by co-targeting of OxPhos.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0818
Sci Adv. 2026 May;12(18): eaed8013

LIPT1 loss confers replication stress and PARP inhibitor sensitivity through PrimPol-mediated ssDNA gaps.

Zengfu Shang, Jui-Chung Chiang, Ching-Cheng Hsu, Ciara Newman, Anthony J Davis, Yuanyuan Zhang.

Replication stress (RS) and altered metabolism are two hallmarks of cancer, yet how metabolic perturbations contribute to RS remains poorly understood. Lipotransferase 1 (LIPT1) catalyzes the covalent attachment of lipoic acid to mitochondrial 2-ketoacid dehydrogenases, sustaining flux through the tricarboxylic acid (TCA) cycle. Loss of LIPT1 causes accumulation of 2-hydroxyglutarate (2-HG), which is known to inhibit α-ketoglutarate (α-KG)-dependent histone demethylases and promotes heterochromatin formation. Here, we show that 2-HG-driven heterochromatin impedes replication fork progression, causing fork stalling and RS in LIPT1-deficient cancer cells. To bypass stalled forks, PrimPol-mediated repriming resumes DNA synthesis but leaves behind single-stranded DNA (ssDNA), which requires poly(adenosine 5'-diphosphate-ribose) polymerase 1 (PARP1) for repair. Furthermore, nascent DNA at reprimed forks undergoes MRE11-dependent degradation, further destabilizing replication fork integrity. Consequently, LIPT1 deficiency promotes replication and genome instability, and therapeutic vulnerability to PARP inhibitor. Together, these findings reveal a mechanistic link between mitochondrial lipoylation and replication fork stability, uncovering a metabolic basis for genome instability in cancer.

DOI: https://doi.org/10.1126/sciadv.aed8013
Cancer Immunol Res. 2026 Apr 29.

Cancer cell-intrinsic SSBP4 enables tumor immune evasion by promoting cholesterol biosynthesis.

Peiqi Ou, Ittai Eres, Junjie Zhao, Chia-Jung Han, Jaehak Oh, Aeryon Kim, Jiayi Dong, Hong Zhou, Tracy Yamawaki, Chi-Ming Li, Andrew Rankin, Rajkumar Noubade, Xin Yu.

The immunosuppressive tumor microenvironment (TME) contributes to resistance against checkpoint inhibitors. However, the precise factors that shape the immune contexture of the TME remain elusive. Here, we report that Single-Stranded DNA Binding Protein 4 (SSBP4), a previously uncharacterized protein, suppresses intratumoral T-cell activation by promoting excessive cholesteryl ester production in tumor cells. Overexpression of SSBP4 in tumor cells decreased T-cell infiltration and accelerated tumor growth in murine syngeneic tumor models. Conversely, genetic ablation of SSBP4 in tumor cells enhanced T-cell infiltration and inhibited tumor growth in a CD8+ T cell-dependent manner. Mechanistically, SSBP4 upregulated cholesterol synthesis genes, leading to increased production of cholesterol and cholesteryl esters in tumor cells, which directly suppressed CD8+ T-cell activation and function. Furthermore, SSBP4 abrogation significantly improved the efficacy of anti-PD-1 treatment. Thus, in this study, we have identified SSBP4 as a cancer cell-intrinsic regulator of cholesterol metabolism that contributes to tumor immune evasion.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-1312
J Hepatol. 2026 Apr 24. pii: S0168-8278(26)00213-8. [Epub ahead of print]

Tim-3 facilitates dendritic cell ferroptosis and impairs anti-tumor immunity in steatohepatitis-related HCC.

Na Li, Xiaojia Song, Xueqi Peng, Mengzhen Li, Mengyao Zhu, Rong Xiao, Liwen Wang, Leyan Ling, Ying Zhao, Tixiao Wang, Zhiyuan Zhou, Zhuanchang Wu, Hua Tang, Lifen Gao, Xiaohong Liang, Chunyang Li, Chunhong Ma.

   BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC) and confers resistance to immunotherapy. However, the underlying mechanisms remain unclear. We aimed to elucidate how the lipid-rich microenvironment of MASLD-HCC drives immune suppression and to identify actionable targets.
METHODS: DC-CD8+ T cell interaction in HCC tissues was analyzed by multiplexed immunofluorescence staining. Mechanistic studies employed high-fat diet (HFD)-induced MASLD-HCC mouse models, genetic or pharmacological inhibition of Tim-3, and DC depletion or adoptive transfer. Lipid peroxidation, ferroptosis, and immune interactions were assessed using flow cytometry, transcriptomics, and functional assays. Therapeutic efficacy of Tim-3 blockade, alone or combined with anti-PD-1 or lenvatinib was evaluated in preclinical models.
RESULTS: HFD reshapes the hepatic tumor immune microenvironment by inducing DC depletion and CD8+ T cell dysfunction, facilitating liver tumor progression. In human steatohepatitic-HCC, DC infiltration and DC-CD8+ T cell interactions were markedly impaired, and high DC-specific Tim-3 expression correlated with poor prognosis. Mechanistically, the lipid-rich microenvironment induced DC depletion via Tim-3-dependent lipid peroxidation and ferroptosis. Genetic or pharmacological inhibition of Tim-3 in DCs attenuated lipid peroxidation, restored DC survival and CD8+ T cell activation, and suppressed tumor growth. Moreover, Tim-3 blockade synergizes effectively with both anti-PD-1 and lenvatinib to achieve sustained tumor control.
CONCLUSION: Our findings establish Tim-3 as a pivotal regulator of DC ferroptosis in metabolic liver cancer. Combining Tim-3 blockade with standard therapies represents a promising strategy to restore immune surveillance in metabolic-associated steatohepatitic HCC.
IMPACT AND IMPLICATIONS: Our findings identify Tim-3 as a crucial metabolic immune checkpoint that governs DC ferroptosis and DC-mediated antitumor immunity in metabolic liver cancer. Targeted blockade of Tim-3 in DCs holds great therapeutic potential for the treatment of steatohepatitic HCC, particularly for patients with MASLD-HCC who exhibit resistance to anti-PD-1 therapy.

Keywords:  Hepatocellular carcinoma; Tim-3; dendritic cells; ferroptosis; metabolic dysfunction-associated steatotic liver disease

DOI:  https://doi.org/10.1016/j.jhep.2026.04.010
Cancer Discov. 2026 Apr 29.

Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas.

Christian Felipe Ruiz, Xiangyu Ge, Rylee McDonnell, Sherry S Agabiti, Daniel C McQuaid, Andy Tang, Meera Kharwa, Jennifer Goodell, Rocio Del M Saavedra-Pena, Allison Wing, Guangtao Li, Natasha Pinto Medici, Marie E Robert, Rohan R Varshney, Michael C Rudolph, Fred S Gorelick, John Wysolmerski, Daniel Canals, John D Haley, Matthew S Rodeheffer, Mandar Deepak Muzumdar.

High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0734