bims-meract 2026-03-22 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–03–22
seventeen papers selected by
Andrea Morandi, Università degli Studi di Firenze

The allosteric IDH1 inhibitor ivosidenib overcomes chemoresistance in intrahepatic cholangiocarcinoma models expressing wild-type IDH1.
Therapeutic targeting of tricarboxylic acid cycle and oxidative phosphorylation: a critical analysis of metabolic interventions in cancer treatment.
Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.
Fatty acid oxidation drives acetyl-CoA-dependent H3K9ac reprogramming to promote adaptive resistance to BRAFV600E inhibition in thyroid cancer.
INSIG1/2 succination mediated by the moonlighting function of ADSL promotes lipogenesis and liver tumorigenesis.
PAK5-Mediated Suppression of β-Hydroxybutyrate Production Promotes Breast Cancer Metastasis and Can Be Overcome with Ketogenic Diet.
Vaccinia-related kinase 2 inhibition elicits vulnerability of glutathione metabolism in pancreatic cancer.
Lactylation Converts ABHD6 into a Mitochondrial Regulator that Drives Lenvatinib Resistance in Hepatocellular Carcinoma.
Androgen receptor localisation and protein interactions provide insight into steroid mediated metabolic shifts in endocrine resistant breast cancer.
Comprehensive single-cell metabolic profiling identifies targets to sensitize triple-negative breast cancer to chemo-immunotherapy.
AURKA-mediated destabilization of SAPS3 drives ferroptosis evasion via 7-dehydrocholesterol biosynthesis in colorectal cancer.
A feedback mechanism from prostate cancer cells to macrophages, reinforced by STAT1, regulates tumor progression and resistance to radiotherapy.
Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.
Microenvironmental acidosis drives PARP- and ATM inhibitor resistance in p53 deficient pancreatic cancer.
ATGL sensitizes hepatocellular carcinoma cells to genotoxic drugs by modulating p53 acetylation/phosphorylation status.
STING-driven mitochondrial metabolism reverses cisplatin resistance via MDH2 desuccinylation in non-small cell lung cancer.
Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.

J Clin Invest. 2026 Mar 17. pii: e199730. [Epub ahead of print]

The allosteric IDH1 inhibitor ivosidenib overcomes chemoresistance in intrahepatic cholangiocarcinoma models expressing wild-type IDH1.

Xiuxian Li, Zhixiao Song, Shusheng Lin, Man Luo, Shaoru Liu, Yang Liu, Fapeng Zhang, Leibo Xu, Chao Liu, Honghua Zhang.

  Gemcitabine-based chemotherapy is the standard treatment regime for advanced intrahepatic cholangiocarcinoma (iCCA), but the frequent presence of chemoresistance limits its efficacy. Here, we identified isocitrate dehydrogenase 1 (IDH1) as the crucial target that confers chemoresistance of iCCA to gemcitabine using a druggable CRISPR/Cas9 library. The positive association between IDH1 expression and chemoresistance was revealed in a gemcitabine-treated iCCA cohort and cell-based drug sensitivity assays. Utilizing patient-derived organoids, cell line-derived xenografts, and patient-derived xenografts, we demonstrated that IDH1 knockdown or IDH1 pharmacological inhibition facilitated gemcitabine efficacy in these pre-clinical iCCA models carrying wild-type IDH1 (wtIDH1). Mechanistically, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate and NADPH, thereby coping with the oxidative stress induced by gemcitabine, maintaining cellular redox homeostasis, and ultimately leading to their chemoresistance to gemcitabine. Significantly, ivosidenib, the FDA-approved allosteric IDH1 inhibitor, demonstrated synergistic anti-tumor efficacy with gemcitabine in wtIDH1 pre-clinical iCCA models through boosting intracellular oxidative stress under physiological conditions. The low level of Mg2+, an ion that competitively hinders binding of ivosidenib on wtIDH1, in iCCA tumor microenvironment contributed to the expanded therapeutic window of ivosidenib in patients with iCCA. Our work revealed the potency of combining targeting IDH1 and chemotherapy against wtIDH1 iCCA and other tumors.

Keywords:  Cancer gene therapy; Hepatology; Liver cancer; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI199730
Biochem Pharmacol. 2026 Mar 12. pii: S0006-2952(26)00221-2. [Epub ahead of print] 117888

Therapeutic targeting of tricarboxylic acid cycle and oxidative phosphorylation: a critical analysis of metabolic interventions in cancer treatment.

Yawei Han, Yuhao Wei, Yuanting Xie, Mengzhu Zheng.

  Metabolic reprogramming is a hallmark of cancer cells, characterized by distinct alterations in cellular metabolism that emerge during malignant transformation. Enhanced activities of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in tumor cells support their elevated biosynthetic demands for essential biomolecules, including nucleotides, amino acids, and fatty acids. These cancer-specific metabolic reprogramming not only generates mutant targets that are directly druggable, but also induces targets associated with synthetic lethality effects. In this review, we systematically elucidate the molecular dysregulation mechanism of the TCA cycle and the key enzyme OXPHOS, integrate the preclinical and clinical data of existing dysregulated enzyme inhibitors, and also propose a therapeutic approach using metabolic synthetic lethality as a strategy to overcome the toxicity and acquired resistance of targeted therapies in order to achieve selective potentiation of cancer cells on top of conventional targeted therapies. Furthermore, we critically analyze the structural optimization of key inhibitors, providing medicinal chemistry insights into their design, optimization, and mechanisms of action, which are essential for developing next-generation therapeutics with improved efficacy and selectivity. Through comprehensive analysis of altered tumor metabolism, we aim to provide novel insights and perspectives for drug design and target selection in cancer therapeutics.

Keywords:  Cell metabolic; Metabolic synthetic lethality; OXPHOS; TCA cycle

DOI:  https://doi.org/10.1016/j.bcp.2026.117888
Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00174-9. [Epub ahead of print]45(3): 117096

Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.

Kevin C Corn, Shannon E Martello, Vinay K Menon, Lucy S Britto, Kara M Simmons, Youssef K Mohamed, Yoanna I Ivanova, Abtin A Ghelmansaraei, Sara A Weidenbach, Tian Zhu, Evan S Krystofiak, Jamey D Young, Vivian Gama, Marjan Rafat.

  Patients with triple-negative breast cancer (TNBC) experience high recurrence rates despite current interventions, which include radiation therapy (RT). Tumor cells thought to be involved in recurrence may survive in part due to their interactions with irradiated fibroblasts following treatment. How fibroblasts metabolically respond to RT and influence the behavior of TNBC cells is poorly understood. In this study, we demonstrate that irradiated fibroblasts undergo dynamic mitochondrial changes that are regulated by autophagy, resulting in a metabolic profile characterized by high levels of mitochondrial respiration and fatty acid oxidation. These metabolic adaptations lead to a secretory profile that induces an aggressive phenotype in TNBC cells that is mitigated when fibroblast autophagy is blocked. Our work reveals a burgeoning link between post-RT metabolic adaptations in fibroblasts and crosstalk with TNBC cells that promotes a microenvironment conducive to recurrence.

Keywords:  CP: cancer; CP: metabolism; autophagy; fatty acid oxidation; fibroblasts; lipid metabolism; mitochondrial elongation; mitochondrial fusion; mitochondrial respiration; radiation therapy; recurrence; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117096
Cell Death Dis. 2026 Mar 20.

Fatty acid oxidation drives acetyl-CoA-dependent H3K9ac reprogramming to promote adaptive resistance to BRAFV600E inhibition in thyroid cancer.

Xumeng Wang, Jing Zhang, Jimeng Yuan, Liping Wen, Tianxing Ying, Zehang Xu, Zheng Zhou, Shitu Chen, Quan Zhou, Jinghao Sheng, Chi Luo, Lisong Teng, Weibin Wang.

BRAF-targeted therapy is a promising strategy for thyroid cancer. However, its efficacy is limited by drug resistance. This study elucidates the role of fatty acid oxidation (FAO) in mediating adaptive resistance to BRAFV600E inhibition (BRAFi) in thyroid cancer. Through integrated transcriptomic and metabolomic analyses, we demonstrate that BRAFi by vemurafenib (PLX4032) significantly enhances FAO in thyroid cancer cells. The pharmacological inhibition of FAO via thioridazine (Thio) synergizes with BRAFi to suppress tumor growth in vitro, in vivo and in a patient-derived organoid. Mechanistically, this metabolic shift is driven by the upregulation of PGC1α, which enhances FAO. The consequent increase in intracellular acetyl-CoA reprograms the histone H3K9 acetylation (H3K9ac) landscape, thereby epigenetically activating pro-survival genes such as RUNX1. In addition, higher expression of RUNX1 correlates with poorer prognosis in thyroid cancer. Consistently, functional studies confirm RUNX1's oncogenic role, as its knockdown reduces cell proliferation, migration, and invasion. In conclusion, our work reveals a metabolic-epigenetic axis underlying adaptive response to BRAFi and identifies RUNX1 as a novel oncogene in thyroid cancer.

DOI: https://doi.org/10.1038/s41419-026-08575-7
Nat Commun. 2026 Mar 15.

INSIG1/2 succination mediated by the moonlighting function of ADSL promotes lipogenesis and liver tumorigenesis.

Yuran Duan, Shuo Wang, Jianyu Liu, Wenxing Qin, Yuli Shen, Yueru Hou, Xue Sun, Yanni Lin, Zhiqiang Hu, Bofei Dong, Yanli Bi, Huang Yang, Min Li, Liwei Xiao, Qingang Wu, Xueli Bai, Yuhao Wang, Gaopeng Li, Yuan Ding, Zhengwei Mao, Yang Luo, Zhimin Lu, Tong Liu, Daqian Xu, Shijian Liu, Peng Zhan, Zheng Wang.

Aerobic glycolysis supports tumor growth, but how tumor cells sense glucose to coordinate biosynthesis remains largely unclear. Here we show that in hepatocellular carcinoma cells, glucose-activated PKCε phosphorylates the purine synthesis enzyme ADSL, triggering its translocation to the endoplasmic reticulum. ADSL then promotes succination of INSIG1/2, which disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi, the activation of SREBP-1 and the transcription of downstream lipogenesis-related genes, proliferation of tumor cells, and tumorigenesis in mice. Through virtual screening, we identify Elsulfavirine, an approved HIV drug, which blocks ADSL-INSIG interaction and suppresses SREBP-1 activation induced by glucose. Combining Elsulfavirine with Lenvatinib synergistically inhibits tumor growth. Clinically, ADSL phosphorylation and INSIG succination correlate with SREBP-1 activation and poor prognosis in human HCC. In summary, these findings reveal a repurposing mechanism by which tumor cells coordinate glucose metabolism and lipogenesis via a moonlighting function of ADSL and underscore a repurposing strategy for liver cancer therapy.

DOI: https://doi.org/10.1038/s41467-026-70583-0
Cancer Res. 2026 Mar 16. 86(6): 1435-1450

PAK5-Mediated Suppression of β-Hydroxybutyrate Production Promotes Breast Cancer Metastasis and Can Be Overcome with Ketogenic Diet.

Yao Xing, Yuen Tan, Bingtao Hu, Hongyan Zhang, Yanshu Li, Jinyu Zuo, Yidu Liu, Fuyi Han, Shu-Lan Sun, Xu Wang, Yang Li, Feng Li.

The ketogenic diet (KD) is an emerging metabolic approach for enhancing the efficacy of cancer therapy, and the KD is characterized by increased production of ketone bodies, including β-hydroxybutyrate (β-HB). Clarifying the direct effects of β-HB on cancer cells is critical for optimizing the therapeutic potential of KD. In this study, we show that β-HB levels were markedly decreased in tumor tissues and serum from patients with breast cancer, particularly in metastatic patients. Additionally, β-HB supplementation demonstrated potent antitumor effects in breast cancer models in vitro and in vivo. P21-activated kinase 5 (PAK5) inhibited β-HB synthesis by interacting with 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2), a key enzyme in ketone generation, and inducing phosphorylation at Ser138 and Ser311. PAK5-mediated HMGCS2 Ser138 phosphorylation recruited the E3 ubiquitin ligase BMI1, thereby facilitating HMGCS2 degradation, and phosphorylation at Ser311 reduced the enzymatic activity of HMGCS2 by inhibiting SIRT3-dependent deacetylation. Collectively, phosphorylation at these two sites coordinately suppressed the generation of intracellular β-HB. Elevated PAK5 in breast cancer stimulated lymph node metastasis, whereas the expression of HMGCS2, particularly its nonphosphorylatable mutants, inhibited PAK5-driven breast tumor growth and metastasis. Consistently, KD or β-HB treatment could reverse breast cancer progression induced by PAK5. Low HMGCS2 expression and β-HB synthesis were associated with lymph node metastasis and poor clinical outcomes in patients, and PAK5 protein levels positively correlated with HMGCS2 phosphorylation at Ser311 residue in breast cancer tissues. Together, these findings demonstrated that the PAK5-HMGCS2 pathway drives breast cancer metastasis and can be circumvented using a KD.
SIGNIFICANCE: PAK5-mediated phosphorylation of HMGCS2 promotes breast cancer growth and metastasis by inhibiting β-hydroxybutyrate production, revealing the role of PAK5 in ketone metabolism and highlighting a potential therapeutic target for breast cancer metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2174
Cell Death Dis. 2026 Mar 19.

Vaccinia-related kinase 2 inhibition elicits vulnerability of glutathione metabolism in pancreatic cancer.

Sisi Chen, Xiaowei Fu, Tianyue Zhang, Rui Zhou, Long Liu, Liuhai Zeng, Bin Xu, Hengqing Zhu, Zhiyu Li.

Metabolic reprogramming has garnered significant attention in recent years due to its therapeutic potential in cancer treatment. However, identifying responsive tumor subpopulations remains a major obstacle in developing metabolism-targeted therapies, as metabolic vulnerabilities vary among cancers with different oncogene expression profiles. Therefore, elucidating the association between oncogene expression and metabolic characteristics could enable more precise metabolic interventions in clinical settings. Using pharmacological approaches, we demonstrate that VRK2-deficient pancreatic cancer (PC) cells exhibit heightened vulnerability to glutathione (GSH) metabolic pathway inhibition. This susceptibility stems from reduced basal GSH levels caused by impaired plasma membrane expression of SLC7A11. Mechanistically, we reveal that VRK2 inhibition disrupts endoplasmic reticulum (ER)-to-Golgi trafficking of SLC7A11, consequently diminishing GSH biosynthesis and predisposing PC cells to ferroptosis. Collectively, our findings establish a novel link between the oncogene VRK2 and GSH synthesis metabolism, providing a molecular basis for developing stratified metabolic therapies for PC patients.

DOI: https://doi.org/10.1038/s41419-026-08573-9
Cancer Res. 2026 Mar 20.

Lactylation Converts ABHD6 into a Mitochondrial Regulator that Drives Lenvatinib Resistance in Hepatocellular Carcinoma.

Yuening Sun, Chengju Luo, Hui Yang, Jiaxin Ye, Fengliang Song, Quanhua Yi, Wenhao Zou, Yan Huang, Xiangjun Fan, Lei Wang, Yanan Zhang, Qian Ding, Yizhun Zhu, Zhiyuan Tang.

Hepatocellular carcinoma (HCC) frequently develops resistance to lenvatinib, a frontline tyrosine kinase inhibitor. Resistance arises from heterogeneous mechanisms involving metabolic reprogramming and mitochondrial adaptation, implicating regulators of these processes as potential therapeutic targets. Here, we identified α/β hydrolase domain containing 6 (ABHD6) as a critical driver of lenvatinib resistance by perturbing mitochondrial dynamics. Ligand-binding at the S148 catalytic site allosterically controlled a molecular switch between canonical enzymatic and non-canonical scaffolding functions of ABHD6, and the pro-resistance function was independent of catalysis but required an unoccupied catalytic site. In resistant HCC, the Warburg effect elevated lactate, leading to K245 lactylation of ABHD6. This modification triggered the mitochondrial translocation of ABHD6, where it functioned as a scaffold that competitively bound the fission regulator FIS1 and displaced DRP1. Disruption of the fission machinery stabilized hyperfused mitochondria, thereby conferring lenvatinib resistance by suppressing drug-induced apoptosis and ROS generation. Both inhibiting lactate production and enforcing occupancy of the S148 site with substrates or a specific inhibitor blocked formation of the ABHD6-FIS1 complex, reactivated mitochondrial fission, and restored lenvatinib sensitivity. This study identified a lactate-driven functional switch in ABHD6 and established that targeting this allosteric mechanism is an effective therapeutic strategy to overcome lenvatinib resistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4282
NPJ Breast Cancer. 2026 Mar 17.

Androgen receptor localisation and protein interactions provide insight into steroid mediated metabolic shifts in endocrine resistant breast cancer.

Rachel Bleach, Emir Bozkurt, Jingqi Xin, Katherine M Sheehan, Sally Shirran, Stephanie Agbana, Mihaela Ola, Leonie Young, Nicole S Spoelstra, Jennifer K Richer, Ana Cristina Vargas, Leonard D Goldstein, Heloisa H Milloli, Christine L Chaffer, Michael W O'Reilly, Jochen Hm Prehn, Marie McIlroy.

Aromatase inhibitors (AI) are standard therapy for hormone receptor-positive breast cancer in post-menopausal women, yet recurrence remains common. Our previous work suggests that an androgen‑dominated steroid environment may drive AI resistance. Although most androgen research has focused on classical genomic pathways in reproductive tissues, interest is growing in their non‑reproductive functions. In particular, the role of cytoplasmic AR has recently gained attention, and its connection to metabolic modulation remains largely unexplored in the context of breast cancer. Cytoplasmic AR was evaluated in a breast cancer microarray (n = 875), validated in an independent cohort (n = 30), and examined in metastatic biopsies (n = 12). LC‑MS/MS identified AR‑interacting proteins in AI‑resistant cells exposed to adrenal androgens, confirmed by co‑immunoprecipitation and imaging. High cytoplasmic AR predicted poor survival in post‑menopausal patients, especially luminal B cancers (p = 0.0085). AI‑resistant models showed diffuse AR localisation throughout the cytoplasm and nucleus accompanied by increased mitochondrial mass and membrane potential, and elevated oxidative phosphorylation and glycolysis. Label‑free mass spectrometry identified G3BP1, SLIRP and IGFBP5 as AR interactors linked to stress response, metabolic adaptation and ERα repression. The findings of this study highlight the prognostic potential of cytoplasmic AR immunoreactivity in specific breast cancer subtypes and uncover novel cytoplasmic AR protein interactions that may mediate metabolic adaptations during the development of endocrine-resistance.

DOI: https://doi.org/10.1038/s41523-026-00924-1
Cell Rep Med. 2026 Mar 17. pii: S2666-3791(26)00076-5. [Epub ahead of print]7(3): 102659

Comprehensive single-cell metabolic profiling identifies targets to sensitize triple-negative breast cancer to chemo-immunotherapy.

Ying Xu, Xin-Yi Liu, Hang Zhang, Li Chen, Han Wang, Zhi-Ming Shao, Yi Xiao, Yi-Zhou Jiang.

  The treatment of triple-negative breast cancer (TNBC) poses significant challenges, necessitating innovative approaches to identify therapeutic targets. This study presents a cohort of patients with early-stage TNBC receiving neoadjuvant chemotherapy or chemo-immunotherapy, leveraging single-cell RNA sequencing and metabolic analysis to elucidate the impact of metabolic reprogramming on treatment response. Our findings reveal metabolic heterogeneity at levels of metabolic genes, pathways, and fluxes. Cell-type-specific metabolic traits show stronger associations with therapeutic response compared with bulk metabolic features and the proportion of major cell types. We identify a dynamic collaboration between tumor cells and myeloid cells driven by differential glucose utilization and lactate production, which facilitates tumor progression. Monocarboxylate transporter 1 (MCT1) inhibitors disrupt their interaction, enhancing the efficacy of anti-PD-1 and antibody-drug conjugate (ADC) treatments in TNBC mouse models. Overall, our study delineates the single-cell metabolic landscape of TNBC and positions MCT1 as a promising target.

Keywords:  flux; metabolism; precision immunotherapy; single-cell RNA sequencing; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.xcrm.2026.102659
Cell Death Dis. 2026 Mar 16.

AURKA-mediated destabilization of SAPS3 drives ferroptosis evasion via 7-dehydrocholesterol biosynthesis in colorectal cancer.

Jialing Gao, Weijing Zhang, Lulu Chen, Ruihan Pu, Shaoqing Huang, Xiaoxue Wu, Zhenshuang Du, Weiling He, Mei Song.

While ferroptosis induction offers promising avenue for cancer therapeutics, its clinical utility in colorectal cancer (CRC) is limited by pervasive intrinsic resistance mechanisms. Here, we identify Aurora kinase A (AURKA) as a central suppressor of ferroptosis by rewiring cholesterol metabolism. Mechanistically, AURKA phosphorylates and destabilizes its negative regulator SAPS3 at Ser523/524, relieving AMPK suppression. Activated AMPK subsequently inhibits SREBP2 nuclear translocation and DHCR7 transcription, resulting in the accumulation of 7-dehydrocholesterol (7-DHC), a lipid antioxidant that confers ferroptosis resistance. Both genetic and pharmacologic inhibition of AURKA restore ferroptosis sensitivity and enhance chemotherapy efficacy in vitro and in patient-derived xenograft models. Clinically, elevated AURKA expression correlates with poor prognosis and reduced chemotherapy response in CRC patients. These findings delineate a novel AURKA-SAPS3-AMPK-SREBP2 axis that bridges cholesterol homeostasis and ferroptosis evasion, positioning AURKA as a promising therapeutic target for chemosensitization in CRC.

DOI: https://doi.org/10.1038/s41419-026-08549-9
Cell Death Dis. 2026 Mar 19.

A feedback mechanism from prostate cancer cells to macrophages, reinforced by STAT1, regulates tumor progression and resistance to radiotherapy.

Jia-Yin Chen, Yu-Ting Xue, Bin Lin, Xu-Yun Huang, Fei Lin, Dong-Ning Chen, Wan-Jin Zhang, Yong Wei, Xue-Yi Xue, Qing-Shui Zheng, Zhi-Bin Ke, Ning Xu.

The resistance to radiotherapy of prostate cancer is driven by interactions within the tumor microenvironment, particularly between prostate cancer cells and tumor-associated macrophages, however the underlying mechanisms remain poorly understood. In this study, we found that STAT1 enhanced the transcription of critical glycolytic enzymes, leading to an increase in lactate secretion from prostate cancer cells. Then, the lactate was transported to macrophages via the MCT1 transporter, activating the NFκB1 pathway, which subsequently promoted macrophage polarization to the M2 phenotype and activated the transcription of MCP-1. MCP-1 was secreted from macrophages interacted with the CCR2 receptor on prostate cancer cells, thereby activating the JAK/STAT1 pathway, ultimately contributing to the progression of prostate cancer and its resistance to radiotherapy. Taken together, our findings identified a STAT1/lactate/NFκB1/MCP-1 positive feedback mechanism as a driver of prostate cancer progression and resistance to radiotherapy that functioned by interaction to macrophages, which could be potential therapeutic targets for the advanced prostate cancer.

DOI: https://doi.org/10.1038/s41419-026-08577-5
Cell Rep. 2026 Mar 17. pii: S2211-1247(26)00185-3. [Epub ahead of print]45(4): 117107

Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.

Tonatiuh Montoya, Joyce V Lee, Longhui Qiu, Abigail Krall, Nedas Matulionis, Yurim Seo, Brian N Finck, Robin K Kelley, Heather Christofk, Andrei Goga.

  Liver cancer is a leading cause of cancer-related death due to the shortage of effective therapies, and MYC overexpression defines an aggressive and difficult-to-treat subset of patients. Given MYC's ability to reprogram cancer metabolism and the liver's role in coordinating systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited liver tumorigenesis. In vivo isotope tracing identified alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle and biosynthesis. Finally, treating a MYC-driven liver tumor model with L-cycloserine diminished the frequency of mouse tumor formation and attenuated the growth of established human liver tumors. Thus, we identify a targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.

Keywords:  CP: cancer; CP: metabolism; GPT2; MYC; alanine metabolism; liver cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117107
iScience. 2026 Mar 20. 29(3): 115112

Microenvironmental acidosis drives PARP- and ATM inhibitor resistance in p53 deficient pancreatic cancer.

Renata Ialchina, Thomas René Simonsen, Henriette Berg Andersen, Arnaud Stigliani, Yifan Dai, Jiayi Yao, Tanja Larsen, Dominika Czaplinska, Luis A Pardo, Albin Sandelin, Stine Falsig Pedersen.

  Tumor suppressor p53 inactivation and an acidic microenvironment are pancreatic ductal adenocarcinoma (PDAC) characteristics supporting disease aggressiveness and treatment resistance. Using murine early PDAC (PanIN) organoids and CRISPR-Cas9 knockout (KO) of p53, we show that the molecular acid-base regulation machinery, intracellular pH (pHi), and luminal pH (pHlum) are profoundly altered by p53 KO, which rescues the decreased pHi and pHlum observed in organoids adapted to microenvironment acidity. p53 KO is associated with DNA damage, poly-ADP-ribose-polymerase (PARP) cleavage, and increased expression and/or activity of kinases Ataxia telangiectasia mutated (ATM), Ataxia-telangiectasia-and-Rad3-related (ATR), and checkpoint kinase-1. Whereas p53 KO organoids are sensitive to the combined inhibition of ATM and PARP, acid adaptation partially rescues this phenotype, increasing treatment resistance in a manner partially restored by the combined inhibition of pH-regulatory transporters. We conclude that p53 loss rewires acid-base homeostasis and that microenvironment acidity limits treatment response in p53-deficient PDAC, possibly by increasing cancer cell pH homeostasis capacity.

Keywords:  Microenvironment; Oncology

DOI:  https://doi.org/10.1016/j.isci.2026.115112
Cell Death Discov. 2026 Mar 20.

ATGL sensitizes hepatocellular carcinoma cells to genotoxic drugs by modulating p53 acetylation/phosphorylation status.

Serena Castelli, Angela De Cristofaro, Enrico Desideri, Emanuele Salvi, Fabio Ciccarone, Maria Rosa Ciriolo.

Hepatocellular carcinoma (HCC) accounts for approximately 90% of liver cancer cases. Few therapeutic options are available for HCC patients due to intrinsic drug resistance or the low efficacy of conventional chemotherapeutic drugs, including genotoxic agents. We previously demonstrated that adipose triglyceride lipase (ATGL) is downregulated in HCC and shows anti-neoplastic activity by affecting sensitivity to different therapeutic approaches. On the basis of this evidence, we assessed the contribution of ATGL activity to the modulation of the DNA damage response induced by genotoxic drugs. We modulated ATGL expression via overexpression and silencing in the presence of etoposide and doxorubicin, which are genotoxic drugs. The catalytic activity of ATGL was abrogated by a selective inhibitor (ATGListatin) or the overexpression of the ATGL catalytic mutant. To assess the DNA damage response, we evaluated the phosphorylation of H2AX histones and the post-translational modifications of p53. The sensitivity to genotoxic drugs was assessed by analyzing cell viability and molecular markers associated with cell cycle arrest and cell death. Our results demonstrate that ATGL enhances DNA damage in HCC cells in response to genotoxic stimuli. The underlying molecular mechanism involves ATGL-mediated activation of PPARα/p300 signaling. As a result, we observed an imbalance in p53 acetylation/phosphorylation status that restrains cell cycle arrest and DNA damage repair while promoting apoptotic cell death. In line with the in vitro findings, bioinformatic analyses revealed a strong correlation between ATGL and the PPARα/p300 axis and further demonstrated an enrichment of gene sets associated with cell cycle regulation and DNA damage response in ATGL-high HCC. In conclusion, ATGL levels can be used as a predictive marker of HCC sensitivity to genotoxic insults. The activation of this lipase, or downstream molecular signaling, may thus be exploited to increase the efficacy of chemotherapeutic treatments in HCC.

DOI: https://doi.org/10.1038/s41420-026-03048-4
J Adv Res. 2026 Mar 17. pii: S2090-1232(26)00253-5. [Epub ahead of print]

STING-driven mitochondrial metabolism reverses cisplatin resistance via MDH2 desuccinylation in non-small cell lung cancer.

Man Zhu, Xiaoyu Tang, Zeren Zhu, Wenjun Tang, Yumeng Cheng, Wenjuan Tang, Qianqian Zhang, Longyu Qin, Suyu Zhang, Yanmin Zhang.

   INTRODUCTION: Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC) and remains a leading cause of cancer-related deaths worldwide. This resistance substantially reduces the efficacy of cisplatin and highlights the need for innovative therapeutic strategies.
OBJECTIVES: To identify targets that reverse cisplatin resistance and clarify the underlying mechanisms of action.
METHODS: The key protein stimulator of interferon gene (STING), involved in regulating cisplatin resistance in NSCLC, was identified through proteomics and validated via in vitro and in vivo experiments. The succinylation post-translation modifications (PTMs) pathway and the modified protein malate dehydrogenase 2 (MDH2), associated with STING-mediated reversal of cisplatin resistance, were screened using modification omics analysis. Site-specific mutants were constructed to investigate critical succinylation sites of MDH2. The desuccinylase of MDH2 was identified through co-IP/MS, and the molecular mechanism by which STING regulates the desuccinylase to inhibit MDH2 succinylation was elucidated. Succinylation-mimetic and desuccinylation mutants were generated to explore the role of MDH2 desuccinylation in mitochondrial respiration. Finally, the mechanism by which MDH2 desuccinylation reverses cisplatin resistance in NSCLC was clarified through in vitro and in vivo experiments.
RESULTS: This study demonstrated that STING stabilizes the mitochondrial desuccinylase Sirtuin 5 (SIRT5) by reducing TRIM21-SIRT5 interaction, enhancing its ability to promote desuccinylation of MDH2 at lysine 314. This PTMs impairs MDH2 enzymatic function, leading to mitochondrial respiratory dysfunction, excessive mitochondrial DNA (mtDNA) damage, and activation of the cGAS-STING signaling pathway, ultimately restoring cisplatin sensitivity in resistant NSCLC cells.
CONCLUSION: This study uncovers a previously unrecognized STING/MDH2 desuccinylation feedback loop that integrates metabolic reprogramming with immune activation. The findings provide insights into the underlying mechanisms and identify STING and Succ-MDH2 (Lys 314) as potential therapeutic targets for developing effective strategies against cisplatin-resistant NSCLC.

Keywords:  Cisplatin resistance; MDH2 desuccinylation; Mitochondrial dysfunction; Non-small cell lung cancer; STING; cGAS-STING signaling

DOI:  https://doi.org/10.1016/j.jare.2026.03.032
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2532814123

Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade.

Evan R Abt, Liang Wang, Grigor Varuzhanyan, Jack Freeland, Tian He, Guadalupe M Peña-Garcia, Lauryn Ruegg, Jami McLaughlin, Donghui Cheng, Nikolas G Balanis, Chia-Chun Chen, Yang Xu, Yi Xing, Sanaz Memarzadeh, Caius G Radu, Thomas G Graeber, Owen N Witte.

  Small cell carcinoma is a highly lethal cancer variant often found with neuroendocrine (NE) features, as exemplified by small cell lung cancer and small cell NE prostate cancer (SCPC). A genome-wide CRISPR dependency screen using SCPC models generated through human prostate cell transformation identifies a requirement for the transcription factor E2F3. E2F3 dependency is linked to RB inactivation, a near universal occurrence across small cell cancers. The requirement for E2F3 is shared by RB-deficient cells originating from the prostate, lung, and adnexa. In RB-deficient cancer cells, E2F3 inhibition restrains cell cycle progression, proliferation, and tumor growth in vivo. Inhibition of de novo pyrimidine synthesis limits E2F3 expression and suppresses small cell carcinoma proliferation in culture. Directly or indirectly targeting E2F3 to leverage a pan-cancer synthetic lethality resulting from RB inactivation represents a potential treatment strategy.

Keywords:  RB tumor suppressor; nucleotide metabolism; small cell cancer; synthetic lethality

DOI:  https://doi.org/10.1073/pnas.2532814123