bims-mibica 2026-08-02 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–08–02
seventeen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.
Dual targeting of BCL-XL and MCL-1 exposes a rapid and exploitable apoptotic vulnerability in non-small cell lung cancer.
Transsulfuration links aspartate-asparagine metabolism and redox homeo-stasis to drive tumor growth.
PLK1-mediated phosphorylation of PHGDH reprograms serine metabolism in advanced prostate cancer.
Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts.
Oxidized protein states define metastatic fitness in lung cancer.
The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.
Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis.
Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
Effects of BCL-2 and MCL-1 Inhibition on Apoptotic and Transcriptional Profiles in Acute Myeloid Leukemia.
ACAA2 suppresses aerobic glycolysis and tumor growth by facilitating mitochondrial pyruvate transport in hepatocellular carcinoma.
Mitophagy Inhibition Promotes Survival and Mitochondrial Function in MYC-driven HCC.
Combined inhibition of de novo pyrimidine synthesis and ATR promotes ATF4-mediated cell death in TP53-deficient ALL.
An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes.
Targeted Degradation of MCL-1 by PROTAC Mcl-1 Degrader-1 Exhibits Antiproliferative and Antimigratory Effects and Triggers Mitochondria-Mediated Apoptosis in Colorectal Cancer.
Emerging venetoclax plus hypomethylating agent-based triplet regimens in newly diagnosed acute myeloid leukemia: updates from the 2025 ASH Annual Meeting.

bioRxiv. 2026 Jul 13. pii: 2026.07.10.737821. [Epub ahead of print]

Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.

Matthew T Villaume, Haley E Ramsey, Valeria Impedovo, Michael Davidson, Maria P Arrate, Anand K Singh, Yujin Lee, Anna Skwarska, Yara F Almadani, Natalia Baran, Sovira Chaudhry, Benjamin J Reisman, Eden G TenBarge, Ming Jiang, Sarah Olmstead, Agnieszka E Gorska, Zhiguo Zhao, Andrew J Monteith, Peter M Grace, Brian O Bachmann, Marina Konopleva, Stefano Tiziani, Michael R Savona.

Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F 1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD⁺/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo , a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F 1 -selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.

DOI: https://doi.org/10.64898/2026.07.10.737821
Cell Death Differ. 2026 Jul 29.

Dual targeting of BCL-XL and MCL-1 exposes a rapid and exploitable apoptotic vulnerability in non-small cell lung cancer.

Liyang Wu, Baris Budak, Oihane Ofogo, Ali Jazaeri Jouneghani, Philippe JeanRichard, Daniel Bachmann, Thomas Kaufmann.

Non-small cell lung cancer (NSCLC) is frequently refractory to mitochondrial apoptosis despite oncogenic and therapeutic stress. Although individual anti-apoptotic BCL-2 family members have been implicated in NSCLC survival, it has remained unclear whether this reflects dominant single-protein dependencies or a cooperative pro-survival network. This uncertainty is exacerbated by the high prevalence of p53 mutations, which compromise DNA damage-induced apoptotic signaling. Here, we systematically dissected intrinsic apoptotic dependencies across a panel of human NSCLC cell lines using selective BH3 mimetics targeting BCL-2, BCL-XL or MCL-1. Consistent with previous reports, BH3 mimetics alone provided only limited and heterogeneous sensitization to cisplatin across NSCLC models. Likewise, single-agent inhibition of BCL-2, BCL-XL or MCL-1 elicited weak and variable apoptotic responses. In striking contrast, combined targeting of BCL-XL and MCL-1 was sufficient to trigger rapid, synergistic and irreversible apoptosis in the majority of NSCLC cell lines, even in the absence of genotoxic stress. Commitment to cell death occurred within minutes and was characterized by early mitochondrial outer membrane permeabilization, cytochrome c release and robust effector caspase activation. This apoptotic response strictly required the intrinsic mitochondrial machinery and BAX/BAK function but was entirely independent of p53 status. Apparent resistance to first-generation (WEHI-539) BCL-XL inhibition in a subset of models reflected incomplete target engagement rather than compensatory survival rewiring. Accordingly, apoptosis was fully restored by next-generation BCL-XL inhibition (A-1331852) or by PROTAC-mediated BCL-XL degradation (DT2216). Importantly, platelet-sparing BCL-XL targeting strategies retained strong synergy with MCL-1 inhibition, addressing a key translational limitation of earlier BH3-mimetic approaches. Together, these data redefine apoptotic control in NSCLC as a cooperative restraint imposed by BCL-XL and MCL-1 rather than discrete, context-dependent dependencies, revealing a rapid, p53-independent mitochondrial apoptotic vulnerability with clear therapeutic implications.

DOI: https://doi.org/10.1038/s41418-026-01829-z
bioRxiv. 2026 Jul 13. pii: 2026.07.10.737826. [Epub ahead of print]

Transsulfuration links aspartate-asparagine metabolism and redox homeo-stasis to drive tumor growth.

Mirko Milosevic, Kristina Dmytruk, Ahmad Alghadi, Pavel Jakoube, Julian Wong Soon, Petra Hyrossova, Muhammad Bin Munim, Sara Isabel Fernandes, Anna Shevzov-Zebrun, Robert Stanko, Isidora Mitric, Zuzana Cockova, Lukas Kucera, Juan Fernández-García, Ales Benda, Bryan Marzullo, Radislav Sedlacek, Jiri Neuzil, Sarah-Maria Fendt, Daniel A Tennant, Matthew G Vander Heiden, Katerina Rohlenova, Jakub Rohlena.

Cytosolic redox balance is tightly coupled to aspartate synthesis through the malate-aspartate shuttle, and limiting the malate-aspartate shuttle has been proposed to constrain tumor growth by restricting aspartate availability. Here we show that tumors derived from cancer cells lacking GOT1 and GOT2, the cytosolic and mitochondrial aspartate aminotransferases essential for as-partate production and malate-aspartate shuttle function, grow despite impaired canonical as-partate synthesis. This is because cytosolic redox state, not aspartate supply, is the primary metabolic bottleneck in GOT1/GOT2 knockout cells. Using single-cell transcriptomics, metabo-lite tracing, and a loss-of-function CRISPR screen, we find that these tumors engage an adaptive bypass in which availability of asparagine, a product of aspartate, enables serine- and methio-nine-dependent transsulfuration to generate α-ketobutyrate, whose reduction regenerates cy-tosolic NAD⁺ and restores redox homeostasis. Pharmacological inhibition or genetic ablation of transsulfuration abrogates this asparagine-driven rescue. These findings define asparagine as a regulator of cytosolic NAD⁺/NADH balance and reveal a link between amino acid metabolism and redox control that suggests transsulfuration as a targetable vulnerability in tumor redox maintenance.
Significance statement: Aspartate synthesis and cytosolic redox balance are both coupled through the malate-aspartate shuttle. We show that the cytosolic NAD⁺/NADH ratio, not aspartate supply, is a critical output of the malate-aspartate shuttle for tumor growth. Availability of asparagine, a product of aspar-tate, enables serine- and methionine-dependent transsulfuration to restore cytosolic NAD⁺/NADH balance, proliferation and tumor growth independently of canonical aspartate pro-duction by the malate-aspartate shuttle. This defines asparagine as a regulator of cytosolic re-dox and identifies transsulfuration as a targetable vulnerability in tumor redox maintenance.

DOI: https://doi.org/10.64898/2026.07.10.737826
Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2618349123

PLK1-mediated phosphorylation of PHGDH reprograms serine metabolism in advanced prostate cancer.

Xiongjian Rao, Derek B Allison, Robert M Flight, Penghui Lin, Daheng He, Zhiguo Li, Yanquan Zhang, Ruixin Wang, Chaohao Li, Jianlin Wang, Xinyi Wang, Jia Peng, Ka Wing Fong, Qing Shao, Chi Wang, Eunus S Ali, Hunter N B Moseley, Xiaoqi Liu.

  Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet their increased biosynthetic and energetic demands. Although cells possess the capacity for de novo serine biosynthesis, most transformed cancer cells preferentially rely on exogenous serine uptake to sustain their growth, yet the regulatory mechanisms driving this metabolic dependency remain poorly understood. Here, we uncover a mechanism by which Polo-like kinase 1 (PLK1), frequently overexpressed in prostate cancer, orchestrates a metabolic shift in serine and sphingolipid metabolism through phosphorylation of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the serine synthesis pathway (SSP). Specifically, PLK1 directly phosphorylates PHGDH at S512, S513, and S517, leading to a marked reduction in its protein level and enzymatic activity. This downregulation of de novo serine biosynthesis forces cancer cells to increase their reliance on exogenous serine uptake via the ASCT2 transporter, which in turn fuels the biosynthesis of lipids, including sphingolipids essential for tumor growth and survival. Our findings suggest that targeting the SSP, serine uptake, or downstream lipid biosynthesis pathways may represent promising therapeutic strategies in advanced cancers characterized by PLK1 dysregulation.

Keywords:  PHGDH; PLK1; metabolism; serine; sphingolipids

DOI:  https://doi.org/10.1073/pnas.2618349123
Cell Rep. 2026 Jul 30. pii: S2211-1247(26)00845-4. [Epub ahead of print]45(8): 117767

Intermembrane coupling between Bcl-xL and the IP3 receptor supports local Ca2+ transfer at ER-mitochondrial contacts.

Arijita Ghosh, David Weaver, Chi Li, Gyӧrgy Hajnóczky.

  Bcl-xL, an anti-apoptotic Bcl-2 family protein, engages laterally with Bak/Bax in the outer mitochondrial membrane (OMM) to inhibit apoptosis and interacts with the IP3 receptor Ca2+ channels (IP3Rs) in the endoplasmic reticulum (ER) membrane to control Ca2+ release. It is unknown if OMM-localized Bcl-xL can also interact in trans with IP3Rs at ER-mitochondrial contacts to form a tethering complex that supports IP3R-mediated local Ca2+ transfer from ER to mitochondria. We establish that IP3R-mitochondria Ca2+ signal propagation depends on Bcl-xL. By targeting Bcl-xL specifically to different subcellular compartments, we find that OMM-localized Bcl-xL increases the efficacy of ER-mitochondrial Ca2+ transfer without changing ER Ca2+ release, despite attenuating mitochondrial Ca2+ uptake. We find interaction between Bcl-xL and each IP3R isoform occurring at the mitochondria and a complex formed by OMM-localized Bcl-xL and IP3Rs. OMM Bcl-xL interacts with IP3Rs in trans at ER-mitochondrial contacts to optimize local Ca2+ signal propagation into the mitochondria.

Keywords:  Bcl-xL; CP: cell biology; CP: metabolism; ERMC; IP3R; calcium signaling; endoplasmic reticulum; local Ca(2+) transfer; mitochondria; organellar crosstalk

DOI:  https://doi.org/10.1016/j.celrep.2026.117767
bioRxiv. 2026 Jul 19. pii: 2026.06.08.730907. [Epub ahead of print]

Oxidized protein states define metastatic fitness in lung cancer.

Maolin Ge, Magdy Gohar, Consuelo Torrini, Yukako Suzuki, Shan Jiang, Yuchen Huang, Benjamin Weinstein, Janice Wong, Naema Nayyar, Md Yousuf Ali, Emily Sullivan, Stefan Harry, Cagri Cakici, Zhuanglin Dai, Nicolò Vivori, Zhi Qiao, Junbing Zhang, Iphia Zhang, Connie Che, Reilly Stevens, Neha Khandelwal, Jinho Jeong, Yue Xu, Sufian Ibrahim, Haoqian Feng, Philipp Haehnel, Christopher W Mount, Maria Martinez-Lage, Lecia Sequist, Chendi Li, Sylvia Azer, Quan Lu, Fan-Yan Wei, Mario L Suvà, Brian B Liau, Aaron N Hata, Edward T Chouchani, A John Iafrate, Michael S Lawrence, Doga Gulhan, Priscilla K Brastianos, Liron Bar-Peled.

Reactive oxygen species (ROS) are a pervasive feature of human cancers, yet the protein targets through which ROS-regulated cell states shape tumor biology remains poorly understood. Here, using cysteine chemical proteomics, we define signatures of protein states under distinct cellular ROS environments that capture protein oxidation and conformational changes. Quantifying these signatures in primary lung tumors and brain metastases revealed a surprising enrichment of oxidative states in metastasis. To determine how these states support fitness, we performed genome-wide CRISPR screens and identified the mitochondrial Complex I subunit NDUFA10 as a key oxidation-dependent vulnerability. Oxidation of NDUFA10•Cys253 supports Complex I function through a previously unrecognized nucleotide kinase activity that maintains mitochondrial DNA levels. Enforcing a reduced conformation in NDUFA10 disrupts brain metastatic colonization in vivo . These findings establish ROS regulated protein states as a functional layer of tumor fitness, providing a framework for identifying redox-dependent mechanisms that support cancer progression.

DOI: https://doi.org/10.64898/2026.06.08.730907
Nat Aging. 2026 Jul 30.

The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming.

Aidan R Cole, Raquel Buj, Apoorva Uboveja, Evan Levasseur, Alexander Tom, Hui Wang, Katarzyna M Kedziora, Adam Chatoff, Andrea Andress Huacachino, Mariola M Marcinkiewicz, Amandine Amalric, Baixue Yang, Naveen Kumar Tangudu, Emily Noonan, Jeff Danielson, Miho Naruse, Amal Taher Elhaw, Sierra White, Danyang Li, Callen T Wallace, Frederick Keeney, Felicia Lazure, Esther Elishaev, Lauren Borho, Hope A Townsend, Robin D Dowell, Aaron Clauset, Dorota E Jazwinska, Matthew S Laird, Huda Atiya, Denarda Dangaj, Lan G Coffman, George Tseng, Steffi Oesterreich, Andrew Kossenkov, Qin Liu, Ana P Gomes, Aditi U Gurkar, Francisco J Schopfer, Francesmary Modugno, Simon C Watkins, Ioannis K Zervantonakis, Benjamin G Bitler, Wayne Stallaert, Nadine Hempel, Nathaniel W Snyder, Katherine M Aird.

Cellular senescence is a consequence of many chemotherapeutics that plays context-dependent roles in cancer. Senescent cells secrete an array of factors collectively known as the senescence-associated secretory phenotype (SASP). Here we show that the cisplatin-induced SASP enhances the detachment of high-grade serous ovarian cancer (HGSOC) cells in vitro and dissemination in vivo. We identify fructose as a metabolic component of the SASP that facilitates cell detachment and show that a high-fructose diet increases HGSOC dissemination in vivo. We identified complex I as the driver of SASP-mediated cell detachment and HGSOC dissemination. Mechanistically, this effect was driven by SASP-mediated inhibition of an NAD+-SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. These findings reveal that the SASP reprograms the metabolic microenvironment, promoting metastatic dissemination in a paracrine fashion, and highlight a pro-tumorigenic metabolic effect of fructose in the SASP that may contribute to the high recurrence rate of HGSOC.

DOI: https://doi.org/10.1038/s43587-026-01172-5
Leukemia. 2026 Jul 31.

Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis.

Chenxi Liao, Jin Wen, Xiao Ma, Nan Wang, Ying Chen, Lei Li, Lingbo Liu, Danyue Peng.

Therapeutic resistance to cytarabine (Ara-C), a cornerstone of acute myeloid leukemia (AML) therapy, remains an unmet clinical need. Here, we identify ACSF2 as a key metabolic determinant of Ara-C resistance. ACSF2 inhibition suppresses Ara-C-resistant AML cell proliferation, restores Ara-C sensitivity in vitro and in vivo. Mechanistically, ACSF2 inhibition impairs cholesterol esterification. Therefore, the increased cholesterol accumulation on mitochondrial membranes results in mitochondrial dysfunction, elevated mitochondrial reactive oxygen species (ROS), and suppression of pro-survival ERK signaling. Furthermore, we first established SREBF1 as a direct transcriptional activator of ACSF2 in this context. Notably, the SREBF1 inhibitor fatostatin synergizes with Ara-C against resistant AML with downregulation of ACSF2. These findings define a crucial role of ACSF2 in Ara-C resistance and highlight the SREBF1-ACSF2 axis as a promising therapeutic target for relapsed/refractory AML.

DOI: https://doi.org/10.1038/s41375-026-03053-7
Sci Adv. 2026 Jul 31. 12(31): eaef0140

Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.

Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.

Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.

DOI: https://doi.org/10.1126/sciadv.aef0140
Medicina (Kaunas). 2026 Jul 22. pii: 1425. [Epub ahead of print]62(7):

Effects of BCL-2 and MCL-1 Inhibition on Apoptotic and Transcriptional Profiles in Acute Myeloid Leukemia.

Giedrė Skliutė, Eigintė Kuklytė, Andrius Žučenka, Veronika Viktorija Borutinskaitė, Rūta Navakauskienė.

  Background and Objectives: Acute myeloid leukemia (AML) is characterized not only by its heterogeneity but also by its high relapse rate. This results in limited treatment options, especially in elderly or therapy-refractory patients. It is known that inhibiting anti-apoptotic BCL-2 family proteins can be effective; however, cellular resistance mechanisms often limit the efficacy of this treatment. We studied the effects of the BCL-2 inhibitor ABT-737, the MCL-1 inhibitor S63845, and their combination on AML cell lines and primary AML patient cells. Materials and Methods: To analyze the effects of ABT-737 and S63845 treatment on cells, cell energy phenotype, apoptosis, and cell cycle were assessed, and gene expression by RT-qPCR and protein levels by Western blot analysis were measured. Results: Treatment with the BCL-2 inhibitor ABT-737, the MCL-1 inhibitor S63845, and their combination reduced AML cell viability and induced apoptosis. Dual treatment also altered the expression of epigenetic regulators, as the levels of DNMT1, EZH2, SUZ12, and HDAC1 were reduced, while histone acetylation was increased. An increase in pro-apoptotic markers (PARP cleavage, caspase-9) was observed, and the expression of oncogenes (MYC, WT1) was reduced in model cell lines and primary AML patient cells. Conclusions: BCL-2 and MCL-1 inhibition, alone or in combination, induced apoptosis and altered the expression of epigenetic regulators and oncogenes in AML cell lines and primary patient cells, with no consistent advantage of combined treatment over single agents. BCL-2/MCL-1 inhibition remains a promising approach for AML, and further work should clarify which patients or disease subtypes are most likely to benefit from combined versus single-agent treatment.

Keywords:  BCL-2; MCL-1; acute myeloid leukemia; apoptosis; cancer

DOI:  https://doi.org/10.3390/medicina62071425
Pathol Res Pract. 2026 Jul 26. pii: S0344-0338(26)00280-3. [Epub ahead of print]286 156627

ACAA2 suppresses aerobic glycolysis and tumor growth by facilitating mitochondrial pyruvate transport in hepatocellular carcinoma.

Yang Liu, Weifang Wang, Shixia Cheng, Jiaxin Zhang, Jibin Li, Bing Wu, Zhe Jing, Tian Xiao.

  Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy characterized by high incidence and mortality rates, representing a major global health challenge. Mounting evidence indicates that metabolic reprogramming contributes substantially to tumor development by promoting cancer cell proliferation and metastasis. However, the underlying mechanisms remain incompletely understood. Acetyl-CoA acyltransferase 2 (ACAA2), a mitochondrial enzyme that catalyzes the final step of fatty acid β-oxidation, plays a key role in cellular acetyl-CoA homeostasis. While acetyl-CoA acts as a pivotal metabolic molecule involved in protein acetylation, whether ACAA2 regulates metabolic reprogramming through acetyl-CoA-mediated mitochondrial protein acetylation remains unclear. In this study, we demonstrate that ACAA2 expression is significantly downregulated in HCC tissues and correlates with poor patient prognosis. Downregulation of ACAA2 promotes HCC cell proliferation and survival without affecting invasive capacity. Mechanistically, ACAA2 downregulation reduces mitochondrial acetyl-CoA levels, thereby decreasing mitochondrial pyruvate carrier 1 (MPC1) acetylation and accelerating its proteasomal degradation, which ultimately impairs mitochondrial pyruvate transport to promote glycolysis and cell proliferation. Collectively, our findings demonstrate a critical tumor-suppressive function of ACAA2 in HCC and suggest it as a potential therapeutic target for the treatment of this malignancy.

Keywords:  ACAA2; Acetylation; Glycolysis; Hepatocellular carcinoma; MPC1

DOI:  https://doi.org/10.1016/j.prp.2026.156627
bioRxiv. 2026 Jul 14. pii: 2026.07.13.738248. [Epub ahead of print]

Mitophagy Inhibition Promotes Survival and Mitochondrial Function in MYC-driven HCC.

Nicholas P Lesner, Laura C Kim, Spencer D Shelton, Madelyn Landis, Xuanyan Cai, Denise Zheng, Tanay Parnaik, Caroline Bartman, M Celeste Simon.

Hepatocellular carcinomas (HCC) are genetically heterogeneous cancers frequently characterized by MYC gene amplification or hyperactivating β-catenin ( CTNNB1 ) mutations. Analysis of TCGA transcriptomics revealed that MYC-driven HCC tumors have decreased expression of mtDNA-encoded genes, but increased expression of nuclear-encoded mitochondrial genes. To investigate this apparent discrepancy, we generated MYC- and CTNNB1-driven murine HCCs, all of which displayed aberrant mitochondrial metabolism. Notably, MYC-driven tumors exhibited significant reductions in OXPHOS and TCA cycle activity that correlated with increased ROS levels, as well as elevated mitochondrial turnover through mitochondrial fission and mitophagy. MYC induces the expression of nuclear respiratory factor 1 (NRF1), which regulates DRP1 and other genes to promote receptor-mediated mitophagy. Knocking out DRP1 reduced mitophagy and ROS levels and promoted survival of HCC-bearing mice. These results identify elevated mitochondrial turnover as a potential therapeutic target in MYC-driven HCC.
Significance: Hepatocellular carcinoma can arise from multiple oncogenes, making targeted therapy more difficult. Here we show that tumors with MYC amplification lose mitochondrial function via fission and mitophagy upregulation. Targeting mitochondrial quality control results in increased survival suggesting a therapeutic window in MYC-driven HCC.

DOI: https://doi.org/10.64898/2026.07.13.738248
Hemasphere. 2026 Jul;10(7): e70439

Combined inhibition of de novo pyrimidine synthesis and ATR promotes ATF4-mediated cell death in TP53-deficient ALL.

Kari J T Grünewald, Marjolein M G Kes, Gawin R Stoll, Willem P J Cox, Dorette S van Ingen Schenau, Enzo M Scutigliani, Emmely M Wagener, Ziqin Tang, Senna Visser, Jolanda Kooiman, Jessica Buijs-Gladdines, Maria Rodionova, Esther A Zaal, Jeroen W A Jansen, Jeroen F van Velzen, Jarno Drost, Laurens T van der Meer, Celia R Berkers, Frank N van Leeuwen.

Mutations or deletions affecting the TP53 gene predict a dismal outcome in relapsed acute lymphoblastic leukemia (ALL). Loss of p53 function compromises the response to many anti-leukemic therapies, underscoring the need for agents that are effective in TP53-deficient cells. Leukemic blasts depend on de novo pyrimidine synthesis to sustain proliferation, and the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) is essential for this pathway. While DHODH inhibitors (DHODHis) show preclinical anti-leukemic activity, the efficacy in TP53-deficient contexts has not been tested. Using both isogenic TP53-wildtype and knock-out cell line models and patient-derived xenografts (PDXs), we show that dual inhibition of DHODH and Ataxia Telangiectasia and Rad3-related (ATR) produces pronounced anti-leukemic effects, irrespective of the TP53 status. Through integrated transcriptomic and metabolomic analyses, we show that combined inhibition of DHODH and ATR leads to a reduced flux of glucose into the TCA cycle, accompanied by an increase in oxidative stress. This metabolic phenotype triggers cell death through a mechanism converging on Activating Transcription Factor 4 (ATF4), a key integrator of cellular responses to metabolic and oxidative stress, which operates largely independently of p53. Taken together, our findings identify ATF4-mediated cell death as a previously unrecognized vulnerability in TP53-deficient ALL.

DOI: https://doi.org/10.1002/hem3.70439
Science. 2026 Jul 30. 393(6810): eads5397

An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.

Thomas Cottle, Lydia Joh, Cori Posner, Adam DeCosta, Dean R Campagna, Mark D Fleming, Sarah Ducamp, Julia R Kardon.

Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.

DOI: https://doi.org/10.1126/science.ads5397
bioRxiv. 2026 Jul 14. pii: 2026.07.13.737885. [Epub ahead of print]

Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes.

Anagha Deshpande, Cho-Ying Chiang, Marlenne Perales, Neha Niranjan, Neelam Sinha, Darren Finlay, Alexandra Stevens, Emily Zahn, Benjamin A Garcia, Irmela Jeremias, Mark Wunderlich, Kristen Jensen-Pergakes, Akshata Udyavar, Amy Carr, Andrew R Nager, Yanling Yang, Rabi Murad, Courtney Jones, Shawn O'Connell, Thomas Paul, Kristiina Vuori, Aniruddha J Deshpande.

Transcriptional condensates anchored by chromatin readers are increasingly recognized as organizing hubs for gene expression, but how their assembly and stability are regulated remains poorly understood. Here, we identify an acetylation-dependent feed-forward circuit that controls the integrity of the Super Elongation Complex (SEC), a key driver of transcriptional elongation. We show that the SAGA histone acetyltransferase catalytic subunits KAT2A/KAT2B license acetylation of both histone H3 lysine 9 (H3K9ac) and SEC components themselves, including ENL, AFF1, and AFF3. Loss of this dual acetylation activity, achieved via a cereblon-recruiting PROTAC (GSK983/GSK699), displaces the chromatin reader ENL from target loci, dissolves ENL-anchored transcriptional condensates, and disrupts SEC-dependent transcriptional output - linking histone and non-histone acetylation to the physical integrity of a core transcriptional machine. Using genome-scale dependency data, we show that the SAGA complex is a selective chromatin dependency in acute myeloid leukemia (AML) AML and hematological malignancies and disrupting this feed-forward transcriptional circuit in AML demonstrates subtype independent antileukemia effects. KAT2A/B degradation drives potent, broad-spectrum antileukemic activity across genetically diverse AML cell lines, primary patient samples, and an isogenic KMT2A-rearranged model bearing cooperating oncogenic mutations, with H3K9ac loss concentrated asymmetrically at core AML oncogene loci such as MYC, MYB, and the HOXA cluster. Together, these findings define an acetylation-dependent circuit governing SEC integrity and establish KAT2A/B degradation as a mechanism-based, pan-AML therapeutic strategy, with implications for transcriptional condensate regulation beyond leukemia.
HIGHLIGHTS: The SAGA complex is a selectively essential chromatin dependency across hematological malignancies and particularly in AMLKAT2A/B degradation drives broad anti-leukemic activity across genetically diverse AML subtypes including chemo-refractory diseaseKAT2A/B degradation depletes H3K9ac at AML oncogene loci and dismantles ENL-anchored condensatesKAT2A/B licenses regulation of super elongation complex acetylation and ENL interaction with SEC complex components.

DOI: https://doi.org/10.64898/2026.07.13.737885
Curr Issues Mol Biol. 2026 Jul 17. pii: 733. [Epub ahead of print]48(7):

Targeted Degradation of MCL-1 by PROTAC Mcl-1 Degrader-1 Exhibits Antiproliferative and Antimigratory Effects and Triggers Mitochondria-Mediated Apoptosis in Colorectal Cancer.

Seher Saruhan, Deniz Özdemir, Can Ali Ağca.

  Myeloid cell leukemia-1 (MCL-1) is a cellular survival protein belonging to the Bcl-2 protein family and is overexpressed in human colorectal cancer (CRC).
BACKGROUND: This study aimed to reduce cancer progression by suppressing the MCL-1 protein using PROTAC MCL-1 Degrader-1 and Trametinib, with the aim of overcoming the apoptosis resistance caused by high MCL-1 expression levels in colorectal cancer cells.
METHODS: Therefore, we tested the cell viability, proliferation, mitochondrial membrane potential, cell cycle progression, and cell death potential of MCL1-specific PROTAC Mcl-1 Degrader-1 and the combination of PROTAC Mcl-1 Degrader-1 and Trametinib in colorectal cancer cell lines using different methods such as WST-8 assays, real-time cell analysis, MMP/JC-1 staining assays, flow cytometry, and Western blot analysis.
RESULTS: The results suggest that PROTAC Mcl-1 Degrader-1 is associated with dose- and time-dependent reductions in cell proliferation in colorectal cancer cells. Under the experimental conditions used in this study, PROTAC MCL-1 Degrader-1 showed limited effects on the migratory potential of colorectal cancer cells but was associated with changes in cell cycle distribution, including an increased proportion of HT-29 cells in the G2/M phase. In addition, combination treatment with PROTAC MCL-1 Degrader-1 and trametinib was associated with greater reductions in cell viability and proliferation than either monotherapy. The combination treatment was also accompanied by changes in mitochondrial membrane potential and increased apoptotic cell populations, with a higher proportion of early apoptotic cells observed in HT-29 and COLO-205 colorectal cancer cell lines.
CONCLUSION: Our findings suggest that the reduction in MCL-1 protein levels observed following PROTAC Mcl-1 Degrader-1 treatment may contribute to its potential therapeutic relevance in colorectal cancer.

Keywords:  MCL-1; PROTAC; apoptosis; colorectal cancer

DOI:  https://doi.org/10.3390/cimb48070733
Exp Hematol Oncol. 2026 Jul 27. pii: 64. [Epub ahead of print]15(1):

Emerging venetoclax plus hypomethylating agent-based triplet regimens in newly diagnosed acute myeloid leukemia: updates from the 2025 ASH Annual Meeting.

Haibo Yu, Ting Shi, Hong-Hu Zhu.

  Venetoclax (VEN) combined with a hypomethylating agent (HMA) has become a standard-of-care frontline therapy for unfit patients with newly diagnosed acute myeloid leukemia (ND AML). The VIALE-A trial established the clinical benefit of VEN plus azacitidine (AZA), with a composite complete remission rate (CRc) of 66.4% and a median overall survival (OS) of 14.7 months. Nevertheless, remission durability remains heterogeneous, and the regimen is non-curative for many patients. Improving remission rates and long-term survival therefore remains an urgent unmet clinical need. VEN/HMA-based triplet regimens incorporating targeted agents are emerging as promising strategies in ND AML, particularly FLT3 inhibitor-based combinations reported at the 2025 American Society of Hematology (ASH) Annual Meeting. Notably, longer-term follow-up data from a study of gilteritinib plus VEN/AZA in patients with ND FLT3-mutated AML showed a median OS of 29.7 months. Additional VEN/HMA-based strategies, including combinations with menin inhibitors and other novel agents, are also being investigated. Here, we provide an overview of the latest clinical updates on VEN/HMA-based triplet regimens in ND AML presented at the 2025 ASH Annual Meeting.

Keywords:  Acute myeloid leukemia; Hypomethylating agents; Newly diagnosed; Triplet regimen; Venetoclax

DOI:  https://doi.org/10.1186/s40164-026-00810-3