bims-mibica 2026-04-26 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–04–26
eighteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Mitochondrial respiration supports cancer growth independent of OXPHOS.
SLC25A48 promotes colorectal cancer growth by enhancing mitochondrial respiration and conferring ferroptosis resistance.
Renal coenzyme A (CoA) production from VB5 fuels stem cell proliferation and tumor growth.
Monocyte-mediated metabolic rewiring via CD31-CD38 interactions promotes growth and drug-resistance in multiple myeloma.
Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.
Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer.
Diet-Induced Hepatic and Mitochondrial Lipid Remodeling Engages One-Carbon Metabolism Under Preserved Mitochondrial Function.
Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway.
The proteomics analysis of mitochondria-enriched fractions reveals alteration of key mitochondrial pathways in breast cancer cell lines.
Tumor suppressor candidate 1 (TUSC1) drives oxidative phosphorylation and tumor cell death in colorectal cancer.
DLAT sustains redox homeostasis and prevent colorectal cancer from ferroptosis by regulating SLC25A39-mediated mitochondrial glutathione transport.
Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.
A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.
Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.
HDAC8 inhibition targets STAT3-MYC axis and synergizes with Venetoclax in KMT2A-rearranged acute myeloid leukemia.
Ubiquitination of glycogen and metabolites in cells and tissues.
CerS2 is a druggable target in triple-negative breast cancer.
Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability.

Biochim Biophys Acta Rev Cancer. 2026 Apr 17. pii: S0304-419X(26)00065-X. [Epub ahead of print] 189593

Mitochondrial respiration supports cancer growth independent of OXPHOS.

Christos Chinopoulos.

  Oxidative phosphorylation is a coordinated process yielding ATP, yet its constituent modules can operate autonomously and support oxygen-dependent, non-OXPHOS reactions that serve cellular proliferation, including neoplasia. Furthermore, even with oxygen present and ETC active, ATP synthesis requires surpassing defined thresholds; thus, respiration is not equivalent to phosphorylation. This review surveys mitochondrial pathways that use the ETC with oxygen as the terminal electron acceptor yet decouple respiration from ATP synthesis. These pathways support tumor progression by sustaining mechanistically distinct respiration-supported currencies, states, and signals, including oxidized coenzyme Q, matrix NAD+, mitochondrial membrane potential, transhydrogenase-derived NADPH, the downstream oxidizing capacity of the CIII-cytochrome c-CIV segment, and ROS as context-dependent outputs. These determinants shape de novo purine and pyrimidine biosynthesis, one‑carbon metabolism, shuttling of reducing equivalents, heme and FeS biogenesis, and proline, choline, and sulfide metabolism, revealing targetable nodes in the respiratory redox network. Therapeutic progress is expected from interventions that collapse the underlying infrastructure - particularly at the coenzyme Q-junction and the CIII-cytochrome c-CIV segment - rather than from strategies aimed solely at ATP deprivation.

Keywords:  Metabolic rewiring; Nucleotide biosynthesis; Oncometabolism; One‑carbon metabolism; Redox homeostasis; Respiratory chain; Tumor metabolism; Ubiquinone; electron transport chain

DOI:  https://doi.org/10.1016/j.bbcan.2026.189593
Free Radic Biol Med. 2026 Apr 20. pii: S0891-5849(26)00427-2. [Epub ahead of print]

SLC25A48 promotes colorectal cancer growth by enhancing mitochondrial respiration and conferring ferroptosis resistance.

Zhen Wang, Jinghu He, E Jifu, Ying Yang, Xiaohong Yang.

  Accumulating evidence indicates that mitochondrial dysfunction is a hallmark of cancer. Nonetheless, the mechanisms linking mitochondrial dysfunction to cancer progression remain largely elusive. SLC25A48 was recently recognized as a transporter involved in mitochondrial choline uptake. Nevertheless, the roles of SLC25A48 in human malignancies remain unexplored. Here, we found that SLC25A48 is elevated in colorectal cancer (CRC) tissues and associates with unfavorable patient outcomes. Functional analyses showed that SLC25A48 accelerates the growth of CRC by enhancing proliferative capacity and preventing cell death. Mechanistically, SLC25A48 exerts its oncogenic function by enhancing the synthesis of choline-derived betaine, which is an important source of one-carbon units for numerous biosynthetic processes. On the one hand, SLC25A48 mitigates oxidative stress-induced ferroptosis by augmenting NADPH availability. On the other hand, it enhances cell proliferation by promoting mitochondrial energy production through upregulating mitochondrial DNA (mtDNA) replication and transcription. Importantly, silencing of SLC25A48 augmented the responsiveness of CRC cells to RSL3-induced ferroptosis and 5-FU-based chemotherapy. Furthermore, increased CTCF expression may contribute, at least in part, to the upregulation of SLC25A48 in CRC. Collectively, our data emphasize that SLC25A48 plays a critical oncogenic role in CRC and holds potential as a druggable target to overcome drug resistance in CRC.

Keywords:  SLC25A48; chemotherapy resistance; colorectal cancer; ferroptosis; mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.136
Nat Commun. 2026 Apr 18.

Renal coenzyme A (CoA) production from VB5 fuels stem cell proliferation and tumor growth.

Ting Miao, Ying Liu, Mujeeb Qadiri, Amaury Dasseux, John M Asara, Yanhui Hu, Xiaomei Sun, Luz Del Carmen Pliego-Alcántara, Christian C Dibble, Norbert Perrimon.

Coenzyme A (CoA), derived from Vitamin B5 (VB5; also called pantothenate), is essential for lipid metabolism, energy production, and cell proliferation. While the intracellular functions of CoA are well-characterized, much less is known about its tissue‑specific regulation and systemic physiological roles. Here, using Drosophila melanogaster, we uncover a gut-renal circuit in which dietary VB5 fuels CoA biosynthesis specifically in the Malpighian tubules (MTs, the fly kidney), non‑autonomously impacting gut homeostasis. We show that, in the MTs, Myc boosts renal CoA production by directly upregulating the pantothenate kinase Fbl (human PANK1-3 ortholog) and downregulating CG5828, which we characterize as the functional ortholog of the metabolite phosphatase and CoA synthesis suppressor PANK4 (dPANK4). Elevated CoA biosynthesis enhances mevalonate-isoprenoid pathway activity in the gut, promoting intestinal stem cell proliferation. We further demonstrate that renal CoA production is required for gut tumor growth in a fly model. Consistently, MYC and genes within the CoA-isoprenoid axis display strong association with clinical outcomes in human cancers. Together, our findings establish that Myc-driven CoA metabolism generates an inter‑organ signal that couples VB5 availability to stem cell control and tumor growth, and identify the CoA-isoprenoid axis as a targetable metabolic vulnerability in cancer.

DOI: https://doi.org/10.1038/s41467-026-71716-1
Hemasphere. 2026 Apr;10(4): e70358

Monocyte-mediated metabolic rewiring via CD31-CD38 interactions promotes growth and drug-resistance in multiple myeloma.

Ramin Raoof, Giada Dal Collo, Helga Simon-Molas, Panagiota Tzortzi, Konxhe Kulaj, Elif N Demirez, Crescenzo Massaro, Renée Poels, Charlotte L B M Korst, Chloe A O'Neill, Wassilis S C Bruins, Marloes E C Broekmans, Payam Behradkia, Maria Krevvata, Sonja Zweegman, Arnon P Kater, Serena R Baglio, Tuna Mutis, Niels W C J van de Donk.

Multiple myeloma (MM) cells interact with different components of the bone marrow (BM) microenvironment, which plays a critical role in MM progression and confers resistance to therapy. Here, we report that monocytes actively control MM cell metabolism by transferring mitochondria to MM cells, thereby increasing their mitochondrial content. Transfer of mitochondria required the expression of CD38 on the surface of MM cells and its ligand CD31 (PECAM-1) on monocytes. The mitochondrial increase in MM cells induced a boost in oxidative phosphorylation (OXPHOS). This monocyte-mediated metabolic adjustment promoted growth, motility, and drug-resistance in both MM cell lines and primary MM cells. Notably, the CD38-targeting monoclonal antibody daratumumab prevented mitochondrial transfer via blocking CD38 on MM cells. Furthermore, in the presence of daratumumab, monocytes acquired a divergent role and obtained mitochondria from MM cells through the process of trogocytosis. Daratumumab-mediated disruption of mitochondrial transfer reduced the mitochondrial content in MM cells, prevented the boost in OXPHOS, significantly impaired MM cell growth and migration, and mitigated drug-resistance. In conclusion, we reveal a crucial metabolic interplay between monocytes and MM cells within the BM microenvironment that promotes tumor growth and induces therapy resistance, providing the rationale for treatment strategies that combine targeting tumor metabolism with existing anti-MM agents.

DOI: https://doi.org/10.1002/hem3.70358
Mol Metab. 2026 Apr 18. pii: S2212-8778(26)00054-2. [Epub ahead of print] 102370

Polyploid cancer cells surviving cisplatin reallocate central 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. Polyploid cancer cells mediate resistance through adaptive cell states transitions that promote survival and tumor recurrence. Here, we investigate metabolic differences between cisplatin-surviving polyploid cells and parental cancer cells using integrated fluxomics. Transcriptomic and proteomic profiling and extracellular flux analyses revealed that surviving cells upregulate glycolysis and gluconeogenesis while reducing oxidative phosphorylation, indicating a shift in central carbon metabolism. Isotope tracing and metabolic modeling demonstrate that surviving cells utilize glucose to fuel the pentose phosphate pathway (PPP) for NADPH generation and metabolize glutamine to provide carbons for the PPP via gluconeogenesis. Integrating our multi-omic datasets into a genome-scale model identified that surviving cells sustain antioxidant metabolism by decreasing fluxes of other NADPH-consuming reactions upon in silico PPP knockout. In addition, pathway-centric transcriptomic analysis revealed that high PPP and antioxidant gene expression correlated with poor survival outcomes in patients across multiple cancer types, demonstrating the clinical prognostic value of PPP and antioxidant metabolism. These findings reveal a systems-level shift in metabolism that maintains antioxidant activity for cell survival, highlighting potential targets and treatment paradigms to overcome therapy resistance.

Keywords:  (13)C-metabolic flux analysis; Cancer metabolism; Chemotherapy resistance; Genome scale metabolic modeling; Integrated fluxomics

DOI:  https://doi.org/10.1016/j.molmet.2026.102370
Cell Death Dis. 2026 Apr 23.

Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer.

Yinong Wang, Bingzhi Wang, Yu Liu, Cheng Zhou, Junhu Yuan, Fanyu Zhang, Ling Ma, Yiming Ma, Hongying Wang.

Glutamine addiction is a key metabolic vulnerability in cancer. However, the mechanisms governing the limited efficacy of glutamine metabolism inhibitor (GMI) monotherapy require further investigation. Via single-cell monitoring using a caspase-3 activity indicator, we identified SLC25A6 as a key mediator of GMI-induced apoptosis in colorectal cancer cells. SLC25A6 overexpression enhanced apoptosis both in vitro and in vivo. SLC25A6 promoted mitochondrial fragmentation and dysfunction and upregulated the expression of mitochondrial fission markers. Notably, mitofission inhibitors largely abolished SLC25A6-related mitochondrial dysfunction and intrinsic apoptosis. Mechanistically, SLC25A6 directly interacted with MIC60, competitively inhibiting MIC19 binding; both MIC60 and MIC19 are key components of the mitochondrial contact site and cristae organizing system (MICOS). The SLC25A6 T126A mutant failed to bind MIC60 and lost its ability to destabilize the MICOS complex and facilitate mitofission. Upregulation of SLC25A6 expression induced by the glutaminase inhibitor CB-839 sensitized cancer cells to the Bcl-2 inhibitor ABT-199. Combined CB-839 and ABT-199 treatment showed strong synergistic antitumor effects in colorectal cancer xenograft models. Our findings reveal a novel function of SLC25A6 that links metabolic stress to mitochondrial apoptosis via disruption of the MICOS complex. Combination treatments with mitochondrial apoptotic inducers represent a promising avenue for maximizing the efficacy of GMIs in cancer treatment.

DOI: https://doi.org/10.1038/s41419-026-08754-6
Free Radic Biol Med. 2026 Apr 21. pii: S0891-5849(26)00321-7. [Epub ahead of print]

Diet-Induced Hepatic and Mitochondrial Lipid Remodeling Engages One-Carbon Metabolism Under Preserved Mitochondrial Function.

Fabrizia Carli, Sara Guerra, Ines Mateus, Riccardo Ducoli, Silvia Sabatini, Samantha Pezzica, Egeria Scoditti, Caroline Dewalle, Véronique Lenoir, Carina Prip-Buus, Amalia Gastaldelli.

   BACKGROUND: Diets rich in saturated fat and sugar drive hepatic steatosis, yet their impact on mitochondrial lipid composition and function remains poorly understood. We investigated how steatotic diets reprogram phospholipid synthesis, remodel the hepatic mitochondrial lipidome, and affect mitochondrial energy metabolism.
METHODS: Mice were fed a high-fat/high-sucrose (HFHS) diet for 20 weeks alongside controls. Lipidomics, metabolomics and metabolic flux analysis using deuterated water (2H2O) were performed via high-resolution mass spectrometry in plasma, liver, and isolated hepatic mitochondria. Mitochondrial respiration was assessed via high-resolution respirometry (OROBOROS). A second cohort was fed a methionine choline-deficient (MCD) diet as a model of altered one-carbon metabolism.
RESULTS: HFHS feeding caused marked hepatic lipid accumulation and extensive remodeling of plasma, liver, and mitochondrial lipidomes, including reduced synthesis of select phosphatidylcholines (PCs). Mitochondrial PCs concentrations were tightly linked to dietary modulation of one-carbon metabolism, which governs PC biosynthesis via methylation. Despite these changes, the mitochondrial PC/PE ratio remained stable and mitochondrial respiration and energy metabolism were preserved. To further evaluate the role of one-carbon metabolism in mitochondrial PC, we evaluated changes during MCD feeding. MCD reduced total mitochondrial lipids, particularly PC and PE synthesis and the mitochondrial PC/PE ratio. Remarkably, mitochondrial function remained intact in both dietary conditions.
CONCLUSION: Steatotic and PC-depleting diets induce substantial remodeling of mitochondrial phospholipids without compromising mitochondrial respiratory capacity. These findings highlight the central role of one-carbon metabolism as a key regulator of mitochondrial membrane homeostasis and underscore the adaptive resilience of mitochondria under dietary and pro-fibrotic stress.

Keywords:  Fluxomics; Hepatic Lipid Remodeling; MASLD Models; Mitochondrial Function; One-Carbon Metabolism

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.031
Genes Dis. 2026 Jul;13(4): 101794

Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway.

Agida Okohi Innocent, Yajie Shen, Yixuan Gao, Ruixin Sun, Kasimujiang Aximujiang, Zizhen Xu, Jinke Cheng, Jiao Ma.

  Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis has been reported in various solid tumor models, its role in leukemogenesis remains elusive. Herein, we demonstrated that UCP2 was highly expressed in AML and significantly associated with poor prognosis and chemoresistance, suggesting that UCP2 can be used as a potential biomarker in acute myeloid leukemia. Mechanistically, in vitro and in vivo silencing of UCP2 significantly impairs acute myeloid leukemia cell growth and survival, accompanied by the disruption of mitochondrial homeostasis. Interestingly, RNA-sequencing analysis and metabolic mass spectrometry revealed that silencing UCP2 resulted in accumulated branched-chain amino acids (BCAAs), which induced oxidative stress through the PI3K/AKT/mTOR signaling pathway. Additionally, the lack of BCAAs restored leukemic cell growth and survival and decreased mitochondrial ROS production induced by inhibiting UCP2. More importantly, supplementation of BCAA enhanced the anti-tumor activity of genipin, a selective inhibitor that targets UCP2, resulting in significantly reduced acute myeloid leukemia blasts, increased mouse survival, and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provides a novel strategy for leveraging the metabolic dependencies of leukemic cells.

Keywords:  AML branched-chain amino acids; Leukemogenesis; Oxidative stress; PI3K/AKT/mTORsignaling; UCP2

DOI:  https://doi.org/10.1016/j.gendis.2025.101794
J Proteomics. 2026 Apr 21. pii: S1874-3919(26)00064-3. [Epub ahead of print]328 105661

The proteomics analysis of mitochondria-enriched fractions reveals alteration of key mitochondrial pathways in breast cancer cell lines.

Hersson David Vázquez-Narváez, María Luisa Labra-Barrios, Emmanuel Ríos-Castro, Carlos Alberto Castañón-Sánchez, Salvador Uribe-Carvajal, Edgar Hernández-Martínez, José Manuel Hernández-Hernández, Gloria León-Ávila, Armando Pérez-Rangel, Erika Beatriz Ángeles-Morales, Juan Pedro Luna-Arias.

  Breast cancer, the leading cause of death in women worldwide, shows significant heterogeneity that makes this disease extremely difficult to treat. Many reports point to metabolic shifts, mainly those carried out into mitochondria, as key processes governing the behavior and heterogeneity of several types of breast cancer. In this study, we performed label-free proteomics analysis on mitochondria-enriched fractions from T47D and MDA-MB-231 breast cancer cell lines, which have distinct molecular classifications, using bioinformatics analyses to identify differentially expressed proteins compared to MCF-12F healthy breast cells. Cancer cells exhibited down-regulated protein levels of subunits from the respiratory chain's Complex I. However, both showed differentially abundant proteins involved in ligase and oxidoreductase activities, including enzymes of glycolysis, pyruvate metabolism, the Krebs cycle, and gluconeogenesis. Many of these enzymes also participate in other metabolic processes, such as mitochondrial localization, mitochondrial gene expression, and the metabolism of amino acids, fatty acids, purines, and pyrimidines. Gene Set Enrichment Analysis revealed that OXPHOS subunits are integrated as signatures of neurodegenerative disease pathways. A protein set with little or no evidence in breast cancer was identified, which could lead to future research in breast cancer mitochondrial metabolism. Data are available via ProteomeXchange with identifier PXD069883. SIGNIFICANCE: This manuscript determined the protein expression profiles of mitochondria-enriched fractions from T47D (Luminal A, stage IV) and MDA-MB-231 (triple negative, Stage IV) breast cancer cell lines compared to the MCF-12F healthy breast cell line. We found that breast cancer cell lines exhibited low expression levels of Complex I subunits from the respiratory chain. However, both breast cancer cell lines presented high expression levels of some proteins related to ligase and oxidoreductase activities, the latter on CH-OH groups in cellular respiration processes, such as some enzymes from glycolysis, pyruvate metabolism, Krebs cycle and gluconeogenesis. Moreover, many of these enzymes also participate in other metabolic processes, such as localization to the mitochondrion, mitochondrial gene expression, amino acid, fatty acid, purine, and pyrimidine metabolism. We also observed through Gene Set Enrichment Analysis that OXPHOS enzymes have a key role in many neurodegenerative disease pathways as well. Finally, we found a protein set with little or no evidence in breast cancer that could lead to future pivotal research in the mitochondrial metabolism of breast cancer.

Keywords:  Differentially expressed proteins; Healthy breast MCF-12F cell line; Label-free proteomics analysis; Mitochondria; T47D and MDA-MB-231 breast cancer cell lines

DOI:  https://doi.org/10.1016/j.jprot.2026.105661
Apoptosis. 2026 Apr 20. pii: 130. [Epub ahead of print]31(5):

Tumor suppressor candidate 1 (TUSC1) drives oxidative phosphorylation and tumor cell death in colorectal cancer.

Janvie Manhas, Ruchi Bhardwaj, Sagar Tyagi, Ramani Shyam Kapuganti, Anushree Bharadwaj, Jaydeep Sharma, Gunjan Sharma, Diksha Joshi, Ayushi Jain, Priyanka Mani, S V S Deo, Rajinder Parshad, Prasenjit Das, Archna Singh, Sam J Mathew, Sudip Sen, Jayanth Kumar Palanichamy.

  Tumor Suppressor Candidate-1 (TUSC1), located at chromosome 9p21.2, resides within a region frequently deleted in human malignancies, yet its role in colorectal cancer (CRC) remains undefined. We investigated TUSC1 expression and function using integrated clinical, transcriptomic, metabolic, and in-vivo approaches. Immunohistochemical analysis of 145 CRC specimens revealed a significant loss of TUSC1 protein compared to normal colon, concordant with TCGA-COAD/READ RNA-Seq datasets. DepMap CRISPR fitness screens demonstrated that TUSC1 is non-essential for baseline proliferation, supporting a tumor suppressor-like profile. Lentiviral re-expression of TUSC1 in low-expressing CRC cell lines (HCT116, SW480) induced broad transcriptomic remodeling, including suppression of PI3K-Akt-mTOR signaling and stemness programs, with concomitant enrichment of oxidative phosphorylation (OXPHOS) pathways. Quantitative proteomics and phospho-western analyses confirmed attenuation of PI3K-Akt signaling. TUSC1 overexpression led to increased mitochondrial respiration, Complex I activity, and mitochondrial mass without significant changes in glycolytic flux. It also led to elevated mitochondrial ROS levels and induced G2/M arrest and apoptosis. Antioxidants partially rescued mitochondrial ROS-dependent cytotoxicity in HCT116 cells, whereas SW480 cells displayed a more limited redox rescue. TUSC1 also reduced cancer stem cell markers, impaired clonogenicity, enhanced 5-fluorouracil sensitivity, and suppressed tumor growth in xenograft models. These findings establish TUSC1 as a metabolic tumor suppressor in CRC that attenuates PI3K-Akt signaling, enhances mitochondrial oxidative metabolism, and promotes ROS-mediated tumor cell death. This study provides the first mechanistic insight into TUSC1's function in cancer, and its restoration or therapeutic induction of oxidative metabolic stress may represent a strategy for targeting CRCs.

Keywords:  Colorectal cancer; Oxidative phosphorylation; TUSC1; Tumor suppressor

DOI:  https://doi.org/10.1007/s10495-026-02336-9
Free Radic Biol Med. 2026 Apr 18. pii: S0891-5849(26)00423-5. [Epub ahead of print]251 229-242

DLAT sustains redox homeostasis and prevent colorectal cancer from ferroptosis by regulating SLC25A39-mediated mitochondrial glutathione transport.

Kun Zhang, Xin Zhang, Chenqi Huang, Junyi Yang, Longxuan Dong, Xijing Chen, Chen Xun, Yongjian Guo.

  Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with limited therapeutic options for advanced-stage patients. Here, we identify DLAT, a key enzyme in mitochondrial metabolism, as a critical driver of CRC progression. Multi-omics analyses revealed that DLAT was overexpressed in CRC tissues and correlated with poor patient prognosis. The results showed that DLAT promoted CRC growth by promoting the resistance to mitochondrial antioxidant stress and suppressing ferroptosis. Mechanistically, DLAT directly bond to the mitochondrial glutathione (mtGSH) transporter SLC25A39 and enhanced its protein stability independent of intracellular GSH levels, leading to the maintain of mitochondrial GSH (mtGSH) import and redox homeostasis. Knockdown of DLAT or SLC25A39 disrupted mtGSH transport, elevated lipid peroxidation, and sensitized CRC cells to ferroptosis. We further identified a small molecular drug GL-V9 as a DLAT degrader. GL-V9 bond to DLAT and induced DLAT degradation through ubiquitin-proteasome pathway. The disruption of DLAT-SLC25A39 axis by GL-V9 led to mtGSH depletion and oxidative stress, as well as the significant suppression of CRC growth. These findings establish DLAT as a metabolic vulnerability in CRC and highlight GL-V9 as a promising therapeutic agent.

Keywords:  Colorectal cancer; DLAT; GL-V9; Mitochondrial GSH transport; SLC25A39

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.133
Redox Biol. 2026 Apr 14. pii: S2213-2317(26)00164-3. [Epub ahead of print]93 104166

Mitochondrial dysfunction triggers a maladaptive peroxisomal response driving lipid accumulation.

Patrícia Coelho, Pedro Dionísio, Vilma Sardão Oliveira, Roberto A Dias, Matthias E Futschik, Robin Klemm, Ira Milosevic, Nuno Raimundo.

  Mitochondria and peroxisomes communicate to maintain lipid homeostasis, but how the latter adjust to mitochondrial dysfunction remains unclear. Here, we show that loss of complex I subunit NDUFS4 in mouse fibroblasts leads to impaired mitochondrial fatty acid oxidation, resulting in the accumulation of triacylglycerol and lipid droplet (LD) expansion. In this context, peroxisomal biogenesis is upregulated, but their β-oxidation capacity is impaired, suggesting an adaptive yet ineffective response. Additionally, lipid overload using a very-long-chain fatty acid (VLCFA) leads to peroxisomal proliferation but prevents LD expansion when peroxisomal β-oxidation is compromised. The data demonstrated that proper peroxisomal processing is necessary for lipid storage under mitochondrial stress conditions. Our findings reveal a peroxisomal maladaptive remodelling response that fails to compensate for mitochondrial dysfunction, leading to disruptions in LD homeostasis. We propose a critical axis involving peroxisomes-LD-mitochondria that buffers metabolic stress in mitochondrial diseases.

Keywords:  Complex I dysfunction; Lipid homeostasis; Mitochondria-peroxisome crosstalk; NDUFS4-KO; Peroxisomes

DOI:  https://doi.org/10.1016/j.redox.2026.104166
Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00187-4. [Epub ahead of print] 102770

A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.

Omid Hajihassani, Asael Roichman, Jacob A Boyer, Michal MacArthur, Ricardo Cordova, Alexander Loftus, Christina S Boutros, Jonathan J Hue, Parnian Naji, Soubhi Tahhan, Peter Gallagher, William Beegan, Danyal Shah, James Choi, Nimat Manzoor, Shihong Lei, Christine Kim, Moeez Rathore, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Craig Hunter, Mehrdad Zarei, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter.

  Pancreatic cancer is the third leading cause of cancer-related death in the United States. Current chemotherapy options provide limited benefits. Emerging evidence suggests that a ketogenic diet (KD) exerts anti-tumor effects by reprogramming tumor metabolism and revealing therapeutic vulnerabilities. Efforts to target glutamine metabolism-an essential pathway in many cancers-have shown promise in preclinical models, but clinical efficacy has remained limited. Here, we show that a KD increases tricarboxylic acid (TCA) cycle activity and elevates reliance on glutamine-related metabolites in murine pancreatic cancer models and in vitro under KD-mimicking conditions. This metabolic adaptation occurs in response to reduced glucose availability. We demonstrate that combining glutamine metabolism inhibitors, such as CB-839 or 6-diazo-5-oxo-L-norleucine (DON), with a KD leads to robust anti-tumor effects in preclinical models of pancreatic cancer. Thus, metabolic vulnerability induced by dietary intervention provides a rationale for combining glutamine-targeted therapies with a ketogenic diet in future clinical studies.

Keywords:  PDAC nutrient flux; chemotherapy; combination therapy; glutamine metabolism; glutamine tracing; ketogenic diet; ketogenic diet media; pancreatic cancer; targeted therapy

DOI:  https://doi.org/10.1016/j.xcrm.2026.102770
FEBS Lett. 2026 Apr 19.

Senescent cells acquire resistance to cystine deprivation-induced ferroptosis via the PPARα-PDK4-phosphorylated PDH axis.

Shiho Machii, Kazushi Morimoto, Pakawit Lerksaipheng, Mirinthorn Jutanom, Ken-Ichi Yamada.

  Cellular senescence, a state of irreversible cell cycle arrest, is implicated in age-related diseases. While it is well known that senescent cells resist apoptosis, studies on their resistance to ferroptosis are limited and not fully understood. Senescent cells remain sensitive to ferroptosis induced by direct inhibition of glutathione peroxidase 4 (GPX4) but resist ferroptosis from cystine starvation, suggesting a role for mitochondrial metabolism. Here, we found that this resistance is mediated by peroxisome proliferator-activated receptor α (PPARα)-dependent upregulation of pyruvate dehydrogenase kinase 4 (PDK4), which inactivates pyruvate dehydrogenase (PDH) and suppresses mitochondria-derived reactive oxygen species, a key driver of ferroptosis. Our findings identify the PPARα-PDK4-PDH axis as a metabolic switch regulating ferroptosis sensitivity in senescent cells and provide insight into the senescence-ferroptosis interaction.

Keywords:  PDH; PDK4; PPARα; cellular senescence; cystine deprivation; ferroptosis; mitochondrial function

DOI:  https://doi.org/10.1002/1873-3468.70332
Leukemia. 2026 Apr 21.

HDAC8 inhibition targets STAT3-MYC axis and synergizes with Venetoclax in KMT2A-rearranged acute myeloid leukemia.

Lianjun Zhang, Wancheng Guo, Yu-Hsuan Fu, Dijiong Wu, Man Li, Ying-Chieh Chen, Chi-Yang Tseng, Wei-Kai Hua, Le Xuan Truong Nguyen, Xin He, Haojie Dong, Lei Zhang, Bin Zhang, Ling Li, Guido Marcucci, Ya-Huei Kuo.

KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is an aggressive AML subtype characterized by 11q23 chromosomal rearrangements involving KMT2A gene and clinically associated with poor prognosis. Herein, we show that HDAC8 is upregulated in KMT2A-r AML and high HDAC8 is associated with poor overall survival in KMT2A-r AML patients. Using a KMT2A::MLLT3 mouse model, we demonstrate that both genetic knockout and pharmacological inhibition of HDAC8 significantly delayed leukemia progression, prolonged survival and reduced disease recurrence. Mechanistically, HDAC8 inhibition downregulates STAT3-MYC axis independent of TP53 status across AML genetic subtypes. Biochemical assays revealed that HDAC8 binds directly to STAT3, promoting its deacetylation and stabilization, while HDAC8-selective inhibitor (HDAC8i) treatment results in increased STAT3 acetylation and subsequent STAT3 degradation which in turn downregulates MYC. Given that STAT3-MYC signaling promotes cell survival and Venetoclax resistance, we show that HDAC8i exhibits synergistic anti-leukemia activity with Venetoclax in primary AML cells regardless of TP53 status. Combination of HDAC8i and Venetoclax synergistically reduced leukemia burden and significantly prolonged survival in both KMT2A::MLLT3 AML and patient-derived xenograft models. This study highlights the regulatory function of HDAC8 on STAT3-MYC and provides the proof-of-principle for targeting HDAC8 in combination with Venetoclax for the treatment of KMT2A-r AML.

DOI: https://doi.org/10.1038/s41375-026-02950-1
Nature. 2026 Apr 22.

Ubiquitination of glycogen and metabolites in cells and tissues.

Marco Jochem, Simon A Cobbold, Craig A Goodman, Catharina Kueng, Anthony Cerra, Laura F Fielden, Man Lyang Kim, Philipp Schenk, Ria Agarwal, Xiangyi S Wang, Simon R Scutts, Michael Pandos, Lin Tang, Thomas Hermanns, Shane M Devine, Martin Brzozowski, Yuri Shibata, Niall D Geoghegan, Catriona A McLean, Bernhard C Lechtenberg, Kay Hofmann, Paul Gregorevic, David Komander.

Ubiquitin signalling covers a vast realm of protein modifications, yet may still be underestimated due to non-proteinaceous substrates, such as sugars, lipids, and nucleotides1 . The breadth of ubiquitinated non-protein substrates, their abundance, and cellular roles are currently unclear, since current ubiquitinomic and proteomic techniques are blind to non-proteinaceous modifications. We report Non-Protein Ub-clipping (NoPro-clipping) as a mass-spectrometry-based technique that combines ubiquitin clippases with sortase labelling. Targeted and untargeted workflows unveil a vast new canvas of ubiquitin modifications in mammalian cells, and in mouse and human tissues. We find ubiquitinated glycogen in any glycogen-containing tissue in mice, with highest abundance in liver and skeletal muscle. Ubiquitination can deliver glycogen to lysosomes, and leads to reduced glycogen levels. Glycogen ubiquitination is modulated in glycogen storage diseases and regulated by the Met1-polyubiquitin machinery. Strikingly, glycogen depletion in the liver during fasting coincides with elevated glycogen ubiquitination, suggesting that ubiquitin is a previously unknown component of physiological glycogen catabolism. We also reveal ubiquitination of endogenous glycerol and spermine in cells and tissues. NoPro-clipping hence unveils unexpected endogenous non-proteinaceous targets of ubiquitination, broadening the role of ubiquitin from a protein modifier to a general modifier of biomolecules.

DOI: https://doi.org/10.1038/s41586-026-10548-x
Mol Cancer Ther. 2026 Apr 21.

CerS2 is a druggable target in triple-negative breast cancer.

Hissah Alatawi, Haritha H Nair, Lingbao Ai, Iqbal Mahmud, Abhishek Gour, Amandeep Singh, Doohyun Baek, Bowen Yan, Chandra K Maharjan, Weizhou Zhang, Brian K Law, Maria Zajac-Kaye, Christopher D Vulpe, Olga A Guryanova, Arun K Sharma, Timothy J Garrett, Abhisheak Sharma, Coy D Heldermon, Sukwon Hong, Satya Narayan.

Triple-negative breast cancer (TNBC) poses a significant therapeutic challenge due to the lack of defined molecular targets. While ceramide synthase 2 (CerS2) has a complex role in oncology, enhancing its enzymatic activity to produce pro-apoptotic, very long-chain ceramides (VLCCs) is a potential anti-cancer strategy. Here, we identify and characterize DH20931, a novel biisoquinoline derivative, as a newly identified small-molecule activator of CerS2. We provide genetic and biochemical evidence that CerS2 is the direct target of DH20931, which shows an effective, receptor-independent cytotoxicity across diverse breast cancer cell lines while sparing normal cells. In vivo, DH20931 demonstrates consistent tumor growth inhibition in both orthotopic xenograft and clinically relevant TNBC patient-derived xenograft (PDX) models, supported by a favorable safety and pharmacokinetic profile. Mechanistically, DH20931 triggers an effective dual mechanism of apoptosis. First, the accumulation of VLCCs induces lipotoxic endoplasmic reticulum (ER) stress, activating the pro-apoptotic ATF4-CHOP pathway. Second, we uncovered a previously unknown physical interaction between CerS2 and the ER calcium channel IP3R1. DH20931 promotes this interaction, enhancing ER-mitochondria proximity and facilitating a marked flux of Ca²⁺ into the mitochondria, which serves as an effective, secondary apoptotic signal. These findings validate CerS2 as a bona fide druggable target and present DH20931 as a promising clinical candidate. This unique synergistic mechanism, coupling lipotoxicity with calcium dysregulation, offers a convincing new strategy for treating aggressive and therapy-resistant breast cancers.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1159
Nat Cell Biol. 2026 Apr 24.

Electrophilic compound screening identifies GPX4-dependent ferroptosis as a senescence vulnerability.

Mariantonietta D'Ambrosio, Matthew E H White, Efthymios S Gavriil, Laura Bousset, Jodie Birch, Aleksandra Gruevska, Emiliano Pasquini, Manuel Colucci, Winnie Fong, Simone Mosole, Aurora Valdata, Dimitris Veroutis, Katie Tyson, Vikas Ranvir, Sandra Prokosch, Joaquim Pombo, Aoki Ardisson, Sanjay Khadayate, George Young, Alex Montoya, Georgia Roumelioti, Jack Houghton, Jianan Lu, Pavel V Shliaha, Elena De Vita, Santiago Vernia, Vassilis G Gorgoulis, Suchira Gallage, Mathias Heikenwälder, Zoe Hall, Andrea Alimonti, Iain A McNeish, Edward W Tate, Jesús Gil.

Senescent cells drive ageing and age-related pathologies, including cancer. Consequently, senolytics, drugs that selectively kill senescent cells, have broad therapeutic appeal. Here we report a senolytic screen of a library of 10,480 electrophilic compounds. Among 38 identified hits, we found a subset of chloroacetamides with broad senolytic activity. Activity-based protein profiling, coupled with functional assays, identified the glutathione peroxidase GPX4 as a target. We show that senescent cells are primed for ferroptosis, displaying high levels of oxidative stress and intracellular Fe2+, but also upregulate GPX4, which prevents the accumulation of oxidized lipids. Treatment with senolytic chloroacetamides or GPX4 inhibitors selectively kills senescent cells by ferroptosis. The combination of anticancer therapies with GPX4 inhibitors eliminated senescent tumour cells in models of melanoma, prostate and ovarian cancer. Our results show that senescent cells rely on GPX4 to prevent ferroptosis and that GPX4 inhibitors kill senescent cells.

DOI: https://doi.org/10.1038/s41556-026-01921-z