bims-meract 2026-01-18 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–01–18
eighteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Cancer might evade immune defences by stealing mitochondria.
Lipid balance and chemoresistance in cancer cells.
Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations.
Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.
Autophagy Cholesterol Axis Remodeling Supports Malignant Progression and Chemoresistance in Glioma.
Chemotherapy resistance due to epithelial-to-mesenchymal transition is caused by abnormal lipid metabolic balance.
Redox-Driven FABP1/PPARγ Signaling Fuels Peroxisomal Fatty Acid Oxidation and Confers Cetuximab Resistance in Drug-Tolerant Head and Neck Cancer Cells.
Intermittent fasting enhances cisplatin-metformin efficacy in therapy-resistant ovarian cancer PDXs.
Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.
Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.
Targeted Lipid Metabolism Screening Uncovers Regulatory Effects on the STING Immune Response in Mevalonate, Eicosanoid and Fatty Acid Pathways.
RAS/MEK/PI3K pathway inhibition augments response to CD40 agonism by targeting CD11b+ Bregs thereby overcoming melanoma PD1-resistance.
Reversing enhancer RNA-mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models.
Glycolysis reprogramming predicts poor prognosis and drives therapy resistance via CLN6 in lethal prostate cancer.
Targeting mitochondrial complexes for cancer therapy.
GCN5-ERK lactylation-phosphorylation loop amplifies lactate-driven cancer progression.
The emerging role of cholesterol metabolism in gynecologic cancer development and therapy.
Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer.

Nature. 2026 Jan 14.

Cancer might evade immune defences by stealing mitochondria.

Laura Dattaro.



Keywords:  Cancer; Immunology; Metabolism

DOI:  https://doi.org/10.1038/d41586-026-00123-9
Elife. 2026 Jan 12. pii: e110231. [Epub ahead of print]15

Lipid balance and chemoresistance in cancer cells.

Kaori Kanemaru, Yoshikazu Nakamura.

  A shift in the balance between two lipids - cholesterol and sphingomyelin - makes hybrid epithelial-mesenchymal cancer cells less responsive to certain chemotherapy drugs.

Keywords:  cancer; cancer biology; cell biology; chemotherapy; cholesterol; epithelial-mesenchymal transition; human; mouse; snail; sphingomyelins

DOI:  https://doi.org/10.7554/eLife.110231
Signal Transduct Target Ther. 2026 Jan 16. 11(1): 33

Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations.

Philipp Hafner, Steffen J Keller, Xun Chen, Asma Alrawashdeh, Huda Jumaa, Friederike I Nollmann, Solène Besson, Judith Kemming, Oliver Gorka, Tonmoy Das, Bismark Appiah, Ariane Lehmann, Mujia Li, Petya Apostolova, Bertram Bengsch, Robert Zeiser, Stefan Tholen, Oliver Schilling, Olaf Groß, Andreas Vlachos, Uwe A Wittel, Dominik von Elverfeldt, Wilfried Reichardt, Melanie Boerries, Geoffroy Andrieux, Guus J Heynen, Stefan Fichtner-Feigl, Luciana Hannibal, Dietrich A Ruess.

Oncogenic KRAS mutations drive metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC). Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity, and promising dual SHP2/mitogen-activated protein kinase (MAPK) inhibition is currently being tested in clinical trials. Exploitable metabolic adaptations may contribute to invariably evolving resistance. To understand the metabolic changes induced by dual inhibition, we comprehensively tested human and murine PDAC cell lines, endogenous tumor models, and patient-derived organoids, which are representative of the full spectrum of PDAC molecular subtypes. We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency. Anabolic pathways, autophagy and glycolysis were also profoundly altered. However, most strikingly, mitochondrial remodeling was evident, persisting into a therapy-resistant state. The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2/MEK1/2 with glutathione peroxidase (GPX4) inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS. The triple combination of SHP2/MEK1/2 inhibition and the ferroptosis-inducing natural compound withaferin A suppressed tumor progression in an endogenous PDAC tumor model in vivo. Our study offers a metabolic leverage point to reinforce RAS pathway interference for targeted PDAC treatment.

DOI: https://doi.org/10.1038/s41392-025-02563-7
Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00501-4. [Epub ahead of print]90 103988

Amino acid restriction sensitizes lung cancer cells to ferroptosis via GCN2-dependent activation of the integrated stress response.

Viktor Antonsson Garellick, Nadia Gul, Parvin Horrieh, Dyar Mustafa, Angana A H Patel, Martin Dankis, Samantha W Alvarez, Johanna Berndtson, Saeed Mahdavi, Maria Schwarz, Andreas Persson, Fikret Zahirovic, Clotilde Wiel, Volkan I Sayin, Per Lindahl.

  Lung cancer cells are vulnerable to iron-dependent oxidation of phospholipids leading to ferroptosis, a process countered by glutathione peroxidase-4 that converts lipid hydroperoxides to lipid alcohols using glutathione as reducing agent. Since ferroptosis-inducing agents are in clinical development, identifying modifiers of ferroptosis susceptibility is warranted. Here, we investigate the impact of amino acids on susceptibility to buthionine sulfoximine (BSO), a glutamate-cysteine ligase inhibitor that blocks biosynthesis of glutathione. We found that reduced amounts of amino acids other than cysteine increased the sensitivity to BSO and other ferroptosis-inducing agents, in a panel of mouse and human lung cancer cells, without affecting glutathione production. Activation of the amino acid sensor protein GCN2 and the integrated stress response lowered the threshold for lipid peroxidation by promoting ATF4-dependent mitochondrial respiration and reactive oxygen species leakage from the electron transport chain under glutathione depletion. The finding provides new insights into lung cancer metabolism and raises the possibility of using amino acid restricted diets in combination with ferroptosis-inducing agents as cancer therapies.

Keywords:  Amino acids; Ferroptosis; Glutathione; Integrated stress response; Lung cancer; Mitochondrial respiration

DOI:  https://doi.org/10.1016/j.redox.2025.103988
bioRxiv. 2026 Jan 07. pii: 2026.01.06.697885. [Epub ahead of print]

Autophagy Cholesterol Axis Remodeling Supports Malignant Progression and Chemoresistance in Glioma.

Shahla Shojaei, Amir Barzegar Behrooz, Kianoosh Naghibzadeh, João Basso, Javad Alizadeh, Tania Dehesh, Roham Sabei, Bhavya Bhushan, Mehdi Eshraghi, Simone C da Silva Rosa, Courtney Clark, Mateusz Marek Tomczyk, Laura Cole, Grant Hatch, Vernon W Dolinsky, Vinith Yathindranath, Donald Miller, Christopher Pasco, Sanjiv Dhingra, Abhay Srivastava, Amir Ravandi, Rui Vitorino, Stevan Pecic, Negar Azarpira, Mahmoud Aghaei, Saeid Ghavami.

Glioma progression and resistance to temozolomide (TMZ) remain major clinical challenges. Here, we investigated whether dysregulated autophagy and cholesterol metabolism are coordinately remodeled during glioma progression and TMZ resistance. Tissue microarray analysis of astrocytoma and glioblastoma specimens revealed progressive autophagosome accumulation, reflected by increased LC3β puncta, coupled with impaired autophagic flux compared with adjacent normal brain tissue. These alterations intensified with tumor grade and were associated with upregulation of farnesyl diphosphate synthase (FDPS), linking malignant progression to cholesterol pathway remodeling. TMZ-resistant (R) glioblastoma cells exhibited epithelial-to-mesenchymal transition, mitotic quiescence, and mitochondrial remodeling consistent with a therapy-tolerant phenotype. Bioenergetic profiling demonstrated reduced respiratory reserve, diminished ATP-linked respiration, and elevated proton leak, indicating constrained metabolic flexibility. In parallel, impaired autophagy flux was associated with suppression of de novo cholesterol synthesis and transcriptional downregulation of SREBP-2 and LDL-R. Comprehensive lipidomic profiling revealed marked cholesterol metabolic reprogramming in R cells, characterized by accumulation of specific cholesteryl esters, including CE 22:5, CE 22:6, CE 22:4, and CE 20:4, despite reduced cholesterol biosynthesis. Pharmacologic inhibition of the mevalonate pathway with simvastatin significantly altered cholesteryl ester profiles but failed to restore autophagy flux or sensitize R cells to TMZ-induced apoptosis, even under combined TMZ-simvastatin treatment.
Lay Abstract: As gliomas progress from astrocytoma to glioblastoma, autophagy becomes dysregulated and cholesterol metabolism is rewired. This coordinated remodeling supports tumor survival, metabolic plasticity, and resistance to temozolomide therapy.
Highlights: Autophagy flux blockade intensifies during progression from astrocytoma to glioblastomaDysregulated autophagy is coupled to altered cholesterol metabolism in malignant gliomasTMZ-resistant glioblastoma cells undergo epithelial-to-mesenchymal transition and mitotic quiescenceResistant cells exhibit constrained bioenergetic capacity and mitochondrial remodelingImpaired autophagy suppresses de novo cholesterol synthesis and lipid recyclingLipidomics reveals accumulation of long-chain cholesteryl esters in TMZ-resistant cellsStatin-based cholesterol inhibition fails to resensitize glioblastoma cells to temozolomide.

DOI: https://doi.org/10.64898/2026.01.06.697885
Elife. 2026 Jan 12. pii: RP104374. [Epub ahead of print]13

Chemotherapy resistance due to epithelial-to-mesenchymal transition is caused by abnormal lipid metabolic balance.

Atsushi Matsumoto, Akihito Inoko, Takuya Tanaka, Gen-Ichi Konishi, Waki Hosoda, Takahiro Kojima, Koji Ohnishi, Junichi Ikenouchi.

  Invasive cancer is defined by the loss of epithelial cell traits resulting from the ectopic expression of epithelial-mesenchymal transition (EMT)-related transcription factors such as Snail. Although EMT is known to impart chemoresistance to cancer cells, the precise molecular mechanisms remain elusive. We found that Snail expression confers chemoresistance by upregulating the cholesterol efflux pump ABCA1 as a countermeasure to the excess of cytotoxic free cholesterol relative to its major interaction partner in cellular membranes, sphingomyelin. This imbalance is introduced by the transcriptional repression of enzymes involved in the biosynthesis of sphingomyelin by Snail. Inhibiting esterification of cholesterol, which renders it inert, selectively suppresses growth of a xenograft model of Snail-positive kidney cancer. Our findings offer a new perspective on lipid-targeting strategies for invasive cancer therapy.

Keywords:  Snail; cancer; cell biology; chemotherapy; cholesterol; epithelial–mesenchymal transition; human; mouse; sphingomyelin

DOI:  https://doi.org/10.7554/eLife.104374
Free Radic Biol Med. 2026 Jan 12. pii: S0891-5849(26)00028-6. [Epub ahead of print]

Redox-Driven FABP1/PPARγ Signaling Fuels Peroxisomal Fatty Acid Oxidation and Confers Cetuximab Resistance in Drug-Tolerant Head and Neck Cancer Cells.

Hang Huong Ling, Chin-Sheng Huang, Ming-Shou Hsieh, Vijesh Kumar Yadav, Iat-Hang Fong, Kuang-Tai Kuo, Chi-Tai Yeh, Jo-Ting Tsai.

  Cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is increasingly recognized as an adaptive state driven by metabolic and redox reprogramming that enables tumor cells to tolerate sustained oxidative and immune stress. Although lipid metabolism and PPARγ signaling have been implicated in therapeutic resistance, their functional contribution to drug-tolerant persister (DTP) cells and the role of peroxisomal fatty acid oxidation (FAO) remain poorly defined. In this study, we demonstrate that a redox-driven FABP1/PPARγ axis sustains peroxisome-centered FAO, GPX4-dependent antioxidant defense, and immune suppression in cetuximab-tolerant HNSCC. FABP1 expression was markedly elevated in cetuximab-tolerant DTP cell models and resistant patient tumors. Genetic silencing or pharmacological inhibition of FABP1 using a selective small-molecule inhibitor impaired tumorsphere formation, increased intracellular reactive oxygen species accumulation, and induced apoptotic cell death, accompanied by coordinated suppression of FAO-associated genes, including CPT1, ACSL family members, and acyl-CoA oxidase 1. In an orthotopic SCC9-DTP xenograft model established in NOD-SCID mice, FABP1 inhibition significantly attenuated tumor growth, disrupted metabolic-redox adaptation, and reduced tumor-associated macrophage polarization toward an immunosuppressive phenotype. Our findings identify the FABP1/PPARγ axis as a central regulator of peroxisome-centered FAO and redox buffering in cetuximab-tolerant DTP cells. Targeting FABP1 collapses this adaptive metabolic-redox program, restores vulnerability to oxidative stress, and alleviates immune suppression, highlighting peroxisomal lipid metabolism as a therapeutically actionable vulnerability in refractory HNSCC.

Keywords:  FABP1; GPX4; HNSCC; PPARγ; cetuximab resistance; fatty acid oxidation; peroxisome; redox homeostasis; tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.020
iScience. 2026 Jan 16. 29(1): 114300

Intermittent fasting enhances cisplatin-metformin efficacy in therapy-resistant ovarian cancer PDXs.

Elena Capellini, Ludovica Perotti, Federica Guffanti, Giulia De Simone, Aurelia Morabito, Anna Maria Ronchi, Laura Sala, Eugenio Scanziani, Daniela Corna, Domenico Cerullo, Cristina Matteo, Robert Fruscio, Laura Brunelli, Giovanna Damia, Francesca Ricci.

  The development of platinum resistance is a significant challenge in the management of ovarian cancer. Targeting the metabolic adaptability of cancer cells and combining dietary interventions with pharmacological treatments are emerging strategies in oncology, enhancing therapy efficacy at low costs. Using ovarian cancer cisplatin-resistant patient-derived xenografts, we showed that repeated cycles of cisplatin plus metformin reversed platinum resistance by remodeling tumor metabolism. Then, based on metabolomic studies, we explored the use of different food approaches, in particular diets with a high vs. a low methionine content and the intermittent fasting regimen, to further stress tumor metabolism and increase the effect of drug treatment. Our findings demonstrated that only intermittent fasting enhanced the antitumor effects of the drug combination and significantly improved the survival, by impairing the tumor energy states. This research highlights the potential of integrating diet-based approaches with pharmacological treatments to overcome platinum resistance in ovarian cancer.

Keywords:  cancer; diet; therapeutics

DOI:  https://doi.org/10.1016/j.isci.2025.114300
bioRxiv. 2026 Jan 06. pii: 2026.01.05.697775. [Epub ahead of print]

Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.

Melvin Li, Bradley Priem, Luke V Loftus, Michael J Betenbaugh, Kenneth J Pienta, Sarah R Amend.

Therapy resistance is the leading cause of cancer-related deaths. Drug-tolerant persister cells (DTPs) represent a major barrier to cancer cure, mediating resistance through adaptive cell state transitions and driving tumor progression. Here, we investigate metabolic differences between DTPs and drug-sensitive cancer cells using integrated fluxomics. Proteomic profiling and extracellular flux analyses revealed that DTPs upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that DTPs utilize glucose to fuel the pentose phosphate pathway (PPP) to generate NADPH and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that DTPs sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. These findings reveal a systems-level shift in DTP metabolism that maintains antioxidant activity for cell survival, highlighting potential new targets and treatment paradigms to overcome therapy resistance.

DOI: https://doi.org/10.64898/2026.01.05.697775
bioRxiv. 2026 Jan 11. pii: 2026.01.09.698662. [Epub ahead of print]

Tumor cell death by ferroptosis contributes to an immunosuppressive tumor microenvironment in syngeneic murine models of cancer.

Nneka E Mbah, Damien Sutton, Hanna S Hong, Rashi Singhal, Rosa E Menjivar, Heather Giza, Peter Sajjakulnukit, Matthew Perricone, Zeribe C Nwosu, Jonathan Alektiar, Jason Lin, Daniel Long, Anthony C Andren, Li Zhang, Howard C Crawford, Timothy L Frankel, Marina Pasca di Magliano, Luigi Franchi, Yatrik M Shah, Costas A Lyssiotis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound metabolic rewiring and a strongly immunosuppressive tumor microenvironment, both of which contribute to poor therapeutic responses. Immunogenic cell death (ICD) represents a potential strategy to overcome immune suppression by coupling tumor cell death to anti-tumor immune activation. Here, we investigated whether targeting amino acid metabolism in PDAC can induce ICD and promote tumor immunity. Through a focused metabolic screen in a panel of syngeneic mouse cancer cell lines, we identified cysteine restriction as a robust inducer of multiple damage-associated molecular patterns (DAMPs) in vitro, hallmark features of ICD. In addition to driving DAMPs, cystine-deprived tumor cells also promoted dendritic cell phagocytosis, maturation, and proinflammatory cytokine production in vitro. Because cysteine deprivation is a known trigger of ferroptosis, we further demonstrated that pharmacologic inhibition of glutathione peroxidase 4 (GPX4) similarly elicited ICD-associated features, which were reversible by the ferroptosis inhibitor Ferrostatin-1. To define additional immune-modulatory signals associated with ferroptosis, we performed metabolomic and lipidomic profiling of cells undergoing, but not yet committed to, ferroptotic death. These analyses revealed selective release of immunosuppressive metabolites and oxidized phospholipids. Consistent with this, conditioned media from ferroptotic cells impaired CD8⁺ T cell proliferation and cytotoxicity in vitro. Thus, together our results indicated that the induction of ferroptotic immunogenic cell death led to the release of both pro- and anti-inflammatory signals. Subsequent analysis in vivo revealed that ferroptotic tumor cells predominantly contributed to a tumor-protective environment. In particular, tumors inoculated with ferroptotic cells were enriched with immunosuppressive myeloid cells and exhibited reduced populations of tumor-infiltrating CD8+ T cells. Further investigation using immune compromised mice suggested that ferroptotic cells may suppress both adaptive and innate immune responses. Collectively, these results underscore the complex and highly context-dependent effects of ferroptosis on tumor immunity, highlighting the critical importance of in vivo models to determine true immunogenic potential within the tumor microenvironment.

DOI: https://doi.org/10.64898/2026.01.09.698662
bioRxiv. 2026 Jan 05. pii: 2026.01.05.697750. [Epub ahead of print]

Targeted Lipid Metabolism Screening Uncovers Regulatory Effects on the STING Immune Response in Mevalonate, Eicosanoid and Fatty Acid Pathways.

Sofia Skobelkina, Ella L Brunsting, Darren J Perkins.

The cGAS/STING pathway is a critical signaling hub that orchestrates type I interferon (IFN) responses, autophagy, and programmed cell death in response to double-stranded DNA (dsDNA) or cyclic dinucleotides. While traditionally characterized as a sensor of foreign or mis-localized self dsDNA, recent evidence demonstrates that STING also integrates information about the homeostasis of cellular lipid biosynthesis into the innate inflammatory response. This integration occurs most notably through STING's sensitivity to de novo cholesterol synthesis. However, given that mammalian cells undergo widespread lipid metabolic reprogramming, characterized by alterations in the synthesis of many lipid species in addition to cholesterol, during processes such as malignant transformation to cancer or during infection by intracellular pathogens, we hypothesized that STING function may be regulated by perturbations in other undescribed lipid pathways. To investigate potential other facets of the STING-lipid interface, we have performed a targeted small molecule screen across multiple lipid metabolic pathways, including the mevalonate, PPAR (fatty acid), and arachidonic acid pathways. Our findings reveal that positively and negatively perturbing enzymes within these diverse lipid paths including lipoxygenases and cyclooxygenases can significantly modulate STING-dependent signal transduction and transcriptional programs, identifying metabolic nodes that link lipid homeostasis with innate immune signaling. These results suggest that existing lipid-lowering and metabolic therapies may have unappreciated immunomodulatory effects on STING applicable in cancer and infectious disease, offering new opportunities for therapeutic intervention.

DOI: https://doi.org/10.64898/2026.01.05.697750
Nat Commun. 2026 Jan 12. 17(1): 162

RAS/MEK/PI3K pathway inhibition augments response to CD40 agonism by targeting CD11b+ Bregs thereby overcoming melanoma PD1-resistance.

Chi Yan, Weifeng Luo, Jinming Yang, Jing Yang, Sheau-Chiann Chen, Kensey Bergdorf, Qianni Hu, Vivian L Weiss, Douglas B Johnson, Qi Liu, Ann Richmond.

Development of effective second-line treatment options for patients with BRAFwtNRASwt or BRAFwtNRASmut melanoma resistant to immune checkpoint blockade (ICB) is crucial. While systemic delivery of agonist CD40 (aCD40) plus anti-PD1 (αPD1) showed activity in patients with ICB-resistant melanoma, the objective response rate was modest (15%), in part due to induction of B regulatory cells (Bregs) which suppress CD8+ effector T cell responses. We previously reported that RAS/RAF/PI3K-inhibition elevates CD40 expression in melanoma cells and sensitizes tumors to ICB. Here, we show that combined treatment with a RAS/PI3K/AKT-pathway inhibitor rigosertib (RGS), and/or a MEK1/2 inhibitor trametinib (T), plus aCD40, overcomes the ICB resistance of BRAFwtNRASwt and BRAFwtNRASmut melanoma tumors growing in C57BL/6 mice. In addition, overexpression of CD40 in these melanoma cells effectively reverses ICB-resistance and aCD40 + αPD1 treatment induces tumor regression. Mechanistically, RGS + T suppress aCD40-associated CD11b+PD-L1+ Bregs, promoting CD8+ T-cell mediated killing in melanoma. scRNA-Seq analyses confirm CD40-associated CD11b+ Bregs across cancer types in patients. Our data demonstrate that addition of RAS/PI3K/AKT and MEK inhibitors to aCD40 resolves the issue of aCD40 induction of CD11b+PD-L1+ Bregs and provides alternative therapeutic options for ICB-resistant BRAFwtNRASwt or BRAFwtNRASmut metastatic melanoma.

DOI: https://doi.org/10.1038/s41467-025-67315-1
J Clin Invest. 2026 Jan 16. pii: e190928. [Epub ahead of print]136(2):

Reversing enhancer RNA-mediated IKBKE gene repression enables synthetic anticancer immunity in prostate cancer models.

Xiang Li, Rui Sun, Hao Li, Jacob J Orme, Xu Zhang, Yu Hou, Sean S Park, Yu Zhang, Yi He, Liguo Wang, Veronica Rodriguez-Bravo, Josep Domingo-Domenech, Shancheng Ren, Dan Xia, Guanghou Fu, Zhankui Jia, Haojie Huang.

  Immunotherapy has been effective in many cancer types but has failed in multiple clinical trials in prostate cancers, with the underlying mechanisms remaining largely unclear. Here, we demonstrate that androgen receptor pathway inhibitor (ARPI) plus irradiation (IR) triggered robust anticancer immunity in prostate cancers in both patients and mice. We show that androgen-activated AR suppressed innate immune signaling by inducing inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) gene repression through HDAC2 interaction with an IKBKE enhancer RNA (IKBKE eRNA, or IKBKE-e). ARPI treatment caused IKBKE derepression and enhanced an IR-induced innate immune response via action of RIG-I and MDA5 dsRNA sensors. IKBKE-e ablation largely enhanced innate immunity in prostate cancer cells in culture and anticancer immunity in mice. Our results revealed AR, HDAC2, and IKBKE eRNA as critical intrinsic immune suppressors in prostate cancer cells, suggesting that rejuvenating inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) signaling by targeting IKBKE-e is an actionable strategy to elicit synthetic anticancer immunity in immunologically "cold" cancers such as prostate cancer.

Keywords:  Immunology; Innate immunity; Oncology; Prostate cancer; Therapeutics

DOI:  https://doi.org/10.1172/JCI190928
Acta Biochim Biophys Sin (Shanghai). 2026 Jan 13.

Glycolysis reprogramming predicts poor prognosis and drives therapy resistance via CLN6 in lethal prostate cancer.

Zhouda Cai, Jianming Lu, Shanshan Mo, Jipu Liu, Chuanfan Zhong, Yongding Wu, Fen Zou, Jianheng Ye, Zhaodong Han, Yuxiang Liang, Le Zhang, Fengping Liu, Weide Zhong.

  Lethal prostate cancer is marked by tumor heterogeneity and resistance to androgen receptor signaling inhibitors (ARSIs). In this study we identify glycolysis as a driver of disease progression and therapy resistance. Using single-sample gene set enrichment analysis (ssGSEA) on the SU2C cohort, we demonstrate that elevated glycolysis activity is associated with poor progression-free and overall survival. The glycolysis-based prognostic score (GLY score) is derived from the HALLMARK_GLYCOLYSIS gene set which includes CLN6, SDHC, B4GALT2, RPE, NANP, and KIF20A, via LASSO-Cox regression. The GLY score effectively stratifies risk in the SU2C and WDCT cohorts, with higher scores predicting worse outcomes and increased SYNE1 mutation frequency. Pan-cancer analysis across TCGA datasets confirm its prognostic value. In vitro, enzalutamide-resistant prostate cancer cell lines exhibit heightened glycolysis, and 2-DG inhibition reverses this effect, restoring drug sensitivity. CLN6 knockdown reduces glycolytic activity and cell proliferation. The GLY score offers robust prognostic value, and CLN6 represents a promising therapeutic target for precision medicine in lethal prostate cancer.

Keywords:  AR signaling inhibitor; CLN6; enzalutamide; glycolysis; lethal prostate cancer

DOI:  https://doi.org/10.3724/abbs.2025257
Biochem Pharmacol. 2026 Jan 10. pii: S0006-2952(26)00026-2. [Epub ahead of print] 117695

Targeting mitochondrial complexes for cancer therapy.

Alaa M A Osman, Alya A Arabi.

  Mitochondrial Complexes I-IV in the electron transport chain (ETC) are strategic targets for cancer treatment since they provide the energy and biosynthetic demands of cancer cells. This review covers in silico, in vitro, and in vivo findings related to the inhibition of ETC complexes in order to block cancer cell survival. It covers details about bioenergetic disruption as well as innovative therapeutic strategies such as photodynamic therapy (PDT). This review, thus, serves as a guide for the development of novel small molecules and repurposed drugs for cancer treatment that target the ETC. In addition, this review shows how deep learning and AI-based nanotechnologies are being applied to predict the oxidative phosphorylation (OXPHOS) activity, identify ETC dependencies in cancer cells, and accelerate the discovery of mitochondrial complex-targeted anticancer drugs. It further explains how targeting ETC complexes can be implemented in precision medicine strategies.

Keywords:  Artificial Intelligence; Cancer; Drug discovery; Electron transport chain; Mitochondria; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.bcp.2026.117695
Nat Chem Biol. 2026 Jan 13.

GCN5-ERK lactylation-phosphorylation loop amplifies lactate-driven cancer progression.

Bingsong Huang, Mingpeng Jin, Gaofeng Cui, Zhe Wang, Feng Wang, Mu Chen, Lei Zhu, Yunxuan Li, Xiaoning Yang, Rui Li, Jinhuan Wu, Linhui Zhai, Yiming He, Jie Yang, Xin Ding, Qianwen Wang, Zhen Xv, Yaobing Ouyang, Jiale Li, Yangbohui Yang, Ke Li, Zhenkun Lou, Georges Mer, Jing Zhang, Yuping Chen, Jian Yuan, Chunlong Zhong.

The Warburg effect leads to increased lactate production and promotes cancer progression but the underlying mechanisms remain unclear. Here, we found that lactate activates the MAPK pathway through ERK lactylation, which promotes cancer progression. We identified GCN5 as the lactyltransferase responsible for ERK lactylation. Activated ERK phosphorylates GCN5, increasing its lactyltransferase activity toward ERK and establishing a positive feedback loop that amplifies lactate-mediated cancer progression. We provide evidence that lactylation of ERK at residue K231 weakens its interaction with MEK, thereby promoting ERK dimerization and activation. We developed a cell-penetrating peptide that specifically inhibits ERK lactylation. This peptide impairs tumor growth in KRAS-mutant cancer models. Taken together, our findings reveal a molecular mechanism by which lactate accelerates cancer progression through the ERK-GCN5 lactylation-phosphorylation cascade and suggest a strategy to disrupt ERK lactylation in RAS-ERK-driven cancers.

DOI: https://doi.org/10.1038/s41589-025-02107-8
Apoptosis. 2026 Jan 10. 31(1): 7

The emerging role of cholesterol metabolism in gynecologic cancer development and therapy.

Hejing Liu, Yujia Zhou, Jiamin Zhang, Liqing Miao, Qianqian Wu, He Zhu, Shuya Pan, Xueqiong Zhu.

  The significance of cholesterol metabolism in cancer is a topic of renewed interest. Cholesterol is an essential factor for mammal cells, for it is not only involved in constituting the cell membrane, but also serves as a precursor to steroid hormones and bile acids. Numerous studies have provided increasing evidence of its high relevance to cancer progression. Targeting cholesterol metabolism by using cholesterol metabolism inhibitors has offered another therapeutic strategy for reversing drug resistance in tumors. Here, the regulatory process of cholesterol homeostasis under normal physiological conditions was introduced. Then, the mechanism by which cholesterol metabolism disorder caused gynecologic cancer development and therapy resistance was summarized. Finally, the therapeutic strategies targeting cholesterol metabolism were also discussed in this review.

Keywords:  Cholesterol metabolism; Gynecological cancer; Therapeutic strategy; Therapy resistance; Tumorigenesis

DOI:  https://doi.org/10.1007/s10495-025-02200-2
Sci Adv. 2026 Jan 16. 12(3): eady5324

Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer.

Diwei Zhao, Zijun Mo, Tianyou Zhang, Xinyang Cai, Zhenyu Yang, Dong Chen, Junliang Zhao, Yuanwei Li, Fangjian Zhou, Zhen Li, Yonghong Li, Jun Wang.

Lactate in the tumor microenvironment (TME) is typically generated by cells exhibiting high glycolytic flux, exemplified by tumor cells. However, in glycolysis-low malignancies such as prostate cancer, stroma-derived lactate may drive noncanonical signaling and functions that remain unclear. Here, we identified APCDD1+ cancer-associated fibroblasts (CAFs) as a distinct stromal population that secretes lactate into the TME in response to androgen deprivation therapy (ADT). Lactate uptake by prostate cancer cells induces androgen receptor variant 7 expression, thereby conferring resistance to ADT. Mechanistically, lactate-induced lactylation of the spliceosome component SNRPA at Lys123 (K123) enhances its recognition of cis-acting elements, increases chromatin binding, and promotes androgen receptor splicing. Targeting lactate transport with monocarboxylate transporter inhibitors effectively restores ADT sensitivity. These findings reveal a metabolic-epigenetic axis linking lactate in the microenvironment to alternative splicing regulation and suggest a promising therapeutic strategy to overcome ADT resistance.

DOI: https://doi.org/10.1126/sciadv.ady5324