bims-mibica 2026-10-18 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–10–18
thirteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Pharmacologically Targeting DHODH-Dependent Pyrimidine Metabolism with HSA-Conjugated BRQ Suppresses Leukemogenesis.
Combining the Telomerase Inhibitor Imetelstat with the BCL-2 Inhibitor Venetoclax Enhances Apoptosis and Improves Survival in Acute Myeloid Leukemia Cellular and Animal Models.
Inhibition of PHB2/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia.
SQOR regulates H2S detoxification and lipid metabolism to maintain glioblastoma metabolic fitness.
Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
Mitochondrial Supercomplex-Associated Proximity Increases in Malignant Glioma Tissue.
Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.
Dynamic protein phosphorylation shapes mitochondrial catalysis, import, and architecture.
Nicotinic acid restriction potentiates NAMPT inhibition in acute myeloid leukemia xenograft models.
Quiescence to proliferation transition regulates asynchronous mitochondrial DNA replication dynamics.
Regulation of PDH via cysteine oxidation on DLAT.
Acute MCL1 Loss via Homoharringtonine-Mediated Translational Inhibition Enables Potent Apoptotic Synergy with BCLXL Blockade.
A natural compound derivative targeting HADHA disrupts mitochondrial homeostasis and suppresses renal cell carcinoma.

Cancers (Basel). 2026 Sep 23. pii: 3091. [Epub ahead of print]18(19):

Pharmacologically Targeting DHODH-Dependent Pyrimidine Metabolism with HSA-Conjugated BRQ Suppresses Leukemogenesis.

Xiaoxu Zhang, Changhao Tian, Yang Ding, Lei Dong, Jia Yu, Rui Su, Min Gao.

  Background: Metabolic reprogramming is a hallmark of acute myeloid leukemia (AML) and provides a rich source of therapeutic vulnerabilities. Among these, de novo pyrimidine biosynthesis has emerged as an important metabolic dependency, yet its contribution to AML progression remains incompletely defined. DHODH, a rate-limiting enzyme in this pathway, represents a promising therapeutic target; however, the clinical development of DHODH inhibitors has been constrained by limited efficacy and dose-limiting toxicity. Thus, defining the mechanistic role of DHODH in AML and developing strategies to improve the therapeutic index of DHODH inhibition remain important unmet needs. Methods: The Cancer Dependency Map (DepMap) database was utilized to identify AML-essential genes that were preferentially required for AML cell survival. Gene set enrichment analysis (GSEA) was used to characterize metabolic dependencies and identify candidate targets. The functional role of DHODH was subsequently evaluated by using genetic knockout in AML cell lines and patient-derived xenograft (PDX) cells. NSGS mice were used in the "human-in-mouse" xenograft mice model. Metabolic profiling coupled with 13C isotope tracing was performed to define DHODH-dependent metabolic alterations, while RNA-seq and genetic rescue assays were used to investigate the mechanisms underlying DHODH-mediated leukemogenesis and ferroptosis. Pharmacologically, we evaluated the DHODH inhibitor BRQ and developed an HSA-based BRQ delivery strategy to improve therapeutic efficacy and reduce systemic toxicity. Results: Our study identified DHODH as a critical vulnerability in AML. DHODH knockout (KO) significantly suppressed AML cell growth, induced apoptosis in vitro, and markedly inhibited AML progression in vivo, supporting a crucial role of DHODH in leukemogenesis. Metabolic profiling further confirmed the dependence of AML cells on DHODH-mediated de novo pyrimidine biosynthesis for leukemic progression. RNA-seq revealed marked activation of the ferroptosis pathway following DHODH KO, with HMOX1 identified as a functionally essential target of DHODH depletion-induced ferroptosis. Pharmacologically, the DHODH inhibitor BRQ phenocopied the antileukemia effects of genetic DHODH depletion both in vitro and in vivo. Of note, we have developed an HSA-based delivery strategy aimed at improving therapeutic efficacy while reducing systemic toxicity. Targeting DHODH, particularly with HSA-conjugated BRQ, represents a promising therapeutic strategy for AML.

Keywords:  PHGDH; acute myeloid leukemia (AML); ferroptosis; human serum albumin (HSA) conjugation; metabolism; therapeutic target

DOI:  https://doi.org/10.3390/cancers18193091
J Clin Med. 2026 Sep 23. pii: 7399. [Epub ahead of print]15(19):

Combining the Telomerase Inhibitor Imetelstat with the BCL-2 Inhibitor Venetoclax Enhances Apoptosis and Improves Survival in Acute Myeloid Leukemia Cellular and Animal Models.

Fei Huang, Joshua J Rusbuldt, Leopoldo Luistro, Heidi Colton, Joseph Eid.

  Background/Objectives: Acute myeloid leukemia (AML) is a heterogeneous disease with limited treatment options. New therapies with novel mechanisms of action are needed. Telomerase and BCL-2 are overexpressed in AML and correlate with disease severity and poor prognosis, suggesting dual targeting may be beneficial. Methods: We evaluated the effect of imetelstat, a telomerase inhibitor, in combination with venetoclax, a BCL-2 inhibitor, in AML cell lines, AML patient-derived samples, and in a MOLM-13 AML xenograft model. Results: In AML cell lines and patient samples, imetelstat plus venetoclax demonstrated dose-dependent synergistic activity to induce apoptosis. Studying AML patient samples ex vivo showed the effect is preferentially in CD34+ leukemic cells, and not in lymphocytes. The synergy induced by venetoclax plus imetelstat was stronger than venetoclax plus hypomethylating agents in AML cell lines. The in vivo MOLM-13 AML xenograft model demonstrated that imetelstat plus venetoclax prolonged survival of tumor-bearing mice compared to either agent alone. Forty percent of mice in the combination group were still alive eighty days after the end of treatment, whereas all mice in the single-agent groups succumbed to disease within two weeks. Mechanisms of synergy elicited by the combination were further illustrated through reduction of hTERT expression and telomerase activity, decreases in the interaction of BCL-2 with BAX, and enhanced mitochondrial dysfunction via loss of mitochondrial membrane potential, and these led to marked increases in the intrinsic mitochondrial apoptosis pathway in AML cells. Conclusions: This study supports the clinical evaluation of imetelstat plus venetoclax for the treatment of AML in the Phase 1 IMAGINE trial (NCT07320235).

Keywords:  BCL-2; acute myeloid leukemia; apoptosis; imetelstat; mechanism of action; synergy; telomerase; venetoclax

DOI:  https://doi.org/10.3390/jcm15197399
Leukemia. 2026 Oct 13.

Inhibition of PHB2/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia.

Romain Vazquez, Maxime Sajot, Jad Nasrallah, Rudy Birsen, Ismaël Boussaid, Morgane Plevenage, Zubaidan Tuerdi, Axelle Guedon, Lilia Cantero Aguilar, Tony Huynh, Natacha Johnson, Chloé Friedrich, Eric Grignano, Justine Decroocq, Lise Willems, Carole Almire, Marie-Clotilde Alves-Guerra, Evelyne Lauret, Yannick Simoni, Michaela Fontenay, Olivier Kosmider, Didier Bouscary, Clement Larrue, Nicolas Chapuis.

Acute myeloid leukemia (AML) cells are highly dependent on mitochondrial activity for survival, with this metabolic reliance driven in part by BCL-2, which is therapeutically targeted by venetoclax-based therapies. The regulation of mitochondrial dynamics in leukemic cells is therefore essential for maintaining mitochondrial homeostasis. However, the mechanisms that enable selective degradation of damaged mitochondria (mitophagy) are still poorly understood in AML. In this study, we sought to elucidate the role of PTEN-induced putative kinase 1 (PINK1), a key sensor of mitochondrial stress, in regulating mitophagy in leukemic cells. Our results identified PINK1 as a central modulator of mitophagy. Genetic depletion of PINK1 reduced both basal and stress-induced mitophagy, leading to mitochondria accumulation and functional impairment. Additionally, we discovered that PINK1 stabilization during mitochondrial stress is regulated by Prohibitin 2 (PHB2), and that depletion or inhibition of PHB2 mirrored the biological effects of PINK1 loss. Notably, both genetic depletion of PINK1 or PHB2, as well as pharmacological inhibition of PHB2, significantly increased AML cell sensitivity to venetoclax both in vitro and in vivo. Together, these findings highlight the potential of targeting the PHB2/PINK1 signalling pathway to improve the efficacy of venetoclax-based therapies in AML by disrupting the mitophagy process.

DOI: https://doi.org/10.1038/s41375-026-03160-5
Res Sq. 2026 Sep 28. pii: rs.3.rs-11077727. [Epub ahead of print]

SQOR regulates H2S detoxification and lipid metabolism to maintain glioblastoma metabolic fitness.

Christopher Hine, András Ponti, Taylor Gatesman, Sarah Hatem, Jordyn Smith, Ishana Senthil, Arjun Akula, Lilly Stanley, Matthew Godwin, Kewal Asosingh, Isaac Ampong, Belinda Willard, Naseer Sangwan, Andrew Dhawan, Daniel Silver, Sameer Agnihotri, Justin Lathia.

Glioblastoma (GBM) adapts to metabolic stress through mitochondrial pathways that are not fully defined. Here, we show sulfide quinone oxidoreductase (SQOR) is upregulated in human GBM and functions as a mitochondrial checkpoint linking hydrogen sulfide (H 2 S) clearance to electron transport chain activity. In patient-derived GBM cells and immunocompetent syngeneic tumors, SQOR channels H 2 S-derived electrons into the ubiquinone pool to sustain oxidative phosphorylation during stress. Genetic or pharmacologic SQOR inhibition causes intracellular H 2 S accumulation, collapse of mitochondrial respiration, tricarboxylic acid cycle dysfunction, and compensatory glycolytic engagement. SQOR loss also redirects carbon into lipid synthesis and storage while impairing lipid mobilization, thereby limiting metabolic flexibility and stem-like cell maintenance. Increasing endogenous H 2 S production further exacerbates the bioenergetic defects caused by SQOR blockade. Functionally, genetic or pharmacologic SQOR inhibition suppresses tumor growth and prolongs survival in vivo . Together, these data identify SQOR-dependent sulfide oxidation as a mitochondrial liability that supports GBM metabolic plasticity.

DOI: https://doi.org/10.21203/rs.3.rs-11077727/v1
J Cell Sci. 2026 Oct 01. pii: jcs265172. [Epub ahead of print]139(19):

Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.

Marina R Hanna, James Costanzo, Madison Yarbrough, Melanie Gil, Matthew Murrow, Vivian Gama.

  Myeloid cell leukemia 1 (MCL-1) is a canonical anti-apoptotic protein crucial for early neurodevelopment. Loss of MCL-1 results in embryonic-lethal neurodevelopmental defects that cannot be rescued by other anti-apoptotic proteins of the B cell lymphoma 2 (BCL-2) family. Here, we pharmacologically inhibit MCL-1 in human neural progenitor cells and find non-apoptotic roles for MCL-1 in sustaining mitochondrial cristae integrity, fatty acid oxidation and neural progenitor identity. MCL-1 inhibition disrupts mitochondrial ultrastructure, leading to a swollen network with disorganized cristae and destabilized OPA1-MICOS machinery that fails to maintain inner mitochondrial membrane architecture. These structural defects are accompanied by displacement of ACSL1 from the outer mitochondrial membrane, impaired fatty acid oxidation, lipid droplet accumulation and reduced mitochondrial oxygen consumption, revealing a tight link between cristae architecture and metabolic competence. Mechanistically, MCL-1 acts through two coordinated functions: maintaining cristae integrity at the inner mitochondrial membrane and retaining ACSL1 at the outer mitochondrial membrane, both independently of caspase activation. Functionally, MCL-1 inhibition selectively depletes intermediate progenitor cells without affecting proliferation, indicating a direct role in lineage progression. Together, our findings position MCL-1 upstream of OPA1, MICOS and ACSL1, and identify it as a critical coordinator of cristae organization, lipid metabolism and neural progenitor fate. This establishes mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlights non-canonical MCL-1 functions as critical regulators of human brain development.

Keywords:  ACSL1; Cristae; Intermediate progenitors; MCL-1; MICOS; Mitochondria; Neural progenitor cells; OPA1

DOI:  https://doi.org/10.1242/jcs.265172
FASEB J. 2026 Oct 31. 40(20): e72363

Mitochondrial Supercomplex-Associated Proximity Increases in Malignant Glioma Tissue.

Minou Tsujishita, Haesoo Bae, Anwaar Ali, Shanmuganathan Balakrishnan, Amina Abulimiti, Nelofer Syed, Kambiz N Alavian.

In rapidly growing tumors, including gliomas, heterogeneous microenvironments with fluctuating oxygen and nutrient availability impose strong selective pressure for metabolic adaptation. For over a century, mitochondria have been recognized as central to the reprogramming of cancer metabolism. However, it remains unclear whether and how remodeling of oxidative phosphorylation (OXPHOS), including organization of electron transport chain (ETC) complexes, contributes to the proliferation of cancer cells. Recent reports suggest that mitochondrial supercomplexes (SCs), higher-order assemblies of ETC complexes, are enriched in tumor cells and may support proliferation by increasing respiratory efficiency and stabilizing electron transfer. Here, we evaluated respiratory SC formation across glioma grades by quantifying ETC complex proximity within mitochondria in patient tissue using proximity ligation assay (PLA). We observed increased PLA signal between ETC complexes I and IV, consistent with increased respirasome assembly, that was associated with malignant glioma (Grades III and IV), and increased proximity between ETC Complexes III and IV that was most prominent in proliferating glioblastoma (Grade IV) cells. Although the precise functions of SCs remain debated, these increases in high-grade glioma relative to Grade II and control tissue suggest that SC remodeling may be a feature of malignant glioma metabolic remodeling.

DOI: https://doi.org/10.1096/fj.202600937RR
Nat Metab. 2026 Oct 14.

Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.

Xingxiu Pan, Austin L Zuckerman, Karl N Miller, Marcos G Teneche, Subrata Munan, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Roya AminiTabrizi, Adarsh Rajesh, Sara Violante, Jiwu Wang, Justin R Cross, Peter D Adams, Hardik Shah, Valentin Cracan.

An elevated NADH/NAD+ ratio (NADH-reductive stress) is a hallmark of mitochondrial dysfunction, yet how it drives pathologies ranging from primary mitochondrial disorders to ageing remains poorly understood1,2. Here, we show that mitochondrial respiratory chain inhibition in primary human fibroblasts induces NADH-reductive stress that coexists with profound NADPH depletion. Using the Escherichia coli soluble transhydrogenase (EcSTH)3 to model this redox coupling in cells with intact mitochondria, we demonstrate that perturbation of both NAD(H) and NADP(H) redox pairs elicits metabolomic and transcriptomic reprogramming, culminating in proliferation arrest with senescence features. Notably, normalizing the NADH/NAD+ ratio alone while NADPH depletion persists fails to rescue proliferation in EcSTH-expressing primary human cells, unlike in transformed HeLa cells. Stable isotope tracing reveals that primary fibroblasts rely more on NADPH-driven reductive carboxylation than HeLa cells, explaining why NADH/NAD+ normalization alone is insufficient for rescue. To test this NADPH dependency, we develop a constitutively active Staphylococcus aureus NAD kinase (SaNADK) that expands the mammalian NADP(H) pool. In fibroblasts, SaNADK restores reductive carboxylation and de novo pyrimidine biosynthesis, and reverses proliferation arrest and senescence features. Furthermore, hepatic SaNADK expression in aged male mice partially alleviates transcriptional signatures of inflammation and metabolic dysregulation. Together, these findings establish EcSTH and SaNADK as xenotopic tools for dissecting NAD(P)H redox coupling and provide a framework for counteracting ageing-associated metabolic decline.

DOI: https://doi.org/10.1038/s42255-026-01640-7
bioRxiv. 2026 Sep 29. pii: 2026.09.28.755151. [Epub ahead of print]

Dynamic protein phosphorylation shapes mitochondrial catalysis, import, and architecture.

Andrew J Smith, Patrick Forny, Sean W Rogers, Merima Forny, David J Pagliarini.

Phosphorylation is a pervasive mitochondrial protein post-translational modification, yet the extent of its influence over mitochondrial functions remains unclear. To identify dynamic mitochondrial phosphoisoforms, we profiled the phosphoproteome of AML12 cells following individual genetic perturbations of 10 resident mitochondrial phosphatases. Guided by these results, we investigated the functional implications of phosphorylation on mitochondrial processes related to catalysis, import, and morphology. We find that phosphorylation of adenylate kinase 2 suppresses its nucleotide binding and catalytic activity. Elevated phosphorylation proximal to the mitochondrial targeting sequence of branched chain ketoacid dehydrogenase kinase disrupts its import and processing, resulting in enhanced catabolism of branched chain amino acids. Most notably, we discover extensive phosphorylation on proteins involved in mitochondrial cristae architecture, including multiple members of the MICOS complex and ATP synthase, upon silencing the phosphatase PGAM5. Collectively, our work connects reversible phosphorylation and resident phosphatases to the regulation of diverse mitochondrial processes.
HIGHLIGHTS: Perturbation of 10 mitochondrial resident phosphatases maps dynamic phosphosites.AK2 S151 phosphorylation tunes catalysis by augmenting adenine nucleotide binding.MTS-proximal BCKDK phosphorylation impairs protein import and gates BCAA catabolism.MIC19 and ATP5I phosphorylation remodels cristae and modulates bioenergetics.

DOI: https://doi.org/10.64898/2026.09.28.755151
Cancer Res Commun. 2026 Oct 12.

Nicotinic acid restriction potentiates NAMPT inhibition in acute myeloid leukemia xenograft models.

Kyoji Tsurumi, Miyuki Nomura, Mai Ohuchi, Ryoma Kizu, Naohiko Kikuchi, Taku Sato, Mami Morita, Yoji Yamashita, Kayoko Hayashi, Tomoyoshi Soga, Yuki Sugiura, Tatsuro Fukuhara, Nobuhiro Tanuma.

NAMPT, a key enzyme in NAD biosynthesis, is a potential therapeutic target in cancer. Acute myeloid leukemia (AML) is among cancer types exhibiting high NAMPT dependence, and elevated NAMPT activity is implicated in venetoclax resistance. Thus, pharmacological NAMPT inhibitors (NAMPTi) have been developed as a promising therapeutic approach in some cancers. However, our current knowledge of in vivo factors that determine NAMPTi therapeutic efficacy is incomplete. Here, using mouse models we found that NAMPTi efficacy against AML is limited by dietary nicotinic acid (NA). Specifically, NA and nicotinic acid riboside (NAR), an NA-derived metabolite, promoted NAD biosynthesis independent of NAMPT and rescued AML cells from NAMPTi-mediated toxicity in vitro. Importantly, in AML xenograft models, dietary NA restriction, which selectively reduces circulating NAR levels, enhanced antitumor efficacy of NAMPTi and prolonged animal survival. Although the combination treatment caused transient hematological toxicity, peripheral blood cell counts largely recovered after treatment. Our findings highlight systemic NAD precursor metabolism, including NAR, as a determinant of responses to NAMPT-targeted therapies. We conclude that NA restriction may improve the therapeutic efficacy of NAMPT inhibitors in AML.

DOI: https://doi.org/10.1158/2767-9764.CRC-26-0274
Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2602028123

Quiescence to proliferation transition regulates asynchronous mitochondrial DNA replication dynamics.

Kiyoshi Miyagawa, Noriko Hosoya.

  Each human cell contains hundreds to thousands of mitochondrial DNA (mtDNA) copies, only a small fraction of which replicates independently of the cell cycle. An asynchronous replication of the leading and lagging strands has been proposed to represent a major replication mode in mitochondria, complicating the investigation of mechanisms that regulate mtDNA replication. Using single-DNA-molecule analysis that distinguishes the origins and timing of replication of each strand, we show that the mitochondrial DNA replication machinery responds to the transition from quiescence to proliferation by dynamically dissociating strand-specific replication rates and modulating the physiological requirements for factors involved in replication and transcription. During this response, the requirement for mitochondrial RNA polymerase (POLRMT) in replication initiation increases, whereas that for primase-polymerase (PrimPol), which is thought to function in DNA repriming at DNA lesions, eventually decreases. Thus, precise quantification of mtDNA replication rates at the single-strand level reveals the temporally dynamic nature of the mtDNA replication machinery during the transition from quiescence to proliferation.

Keywords:  asynchronous replication; mitochondrial DNA; quiescence

DOI:  https://doi.org/10.1073/pnas.2602028123
Nat Commun. 2026 Oct 14. pii: 10784. [Epub ahead of print]17(1):

Regulation of PDH via cysteine oxidation on DLAT.

Fabiola Garcia-Cortizo, Tobias Weber, Hana Nůsková, Daniel Pfaff, Michael Büttner, Angela Wirth, Elisabeth Kliemank, Gernot Poschet, Marc Freichel, Thomas Fleming, Alba Sulaj, Peter Paul Nawroth, Julia Szendroedi, Aurelio A Teleman.

Pyruvate dehydrogenase (PDH) complex is a key regulator of metabolism, controlling flux from glycolysis into the tricarboxylic acid (TCA) cycle. PDH is often dysregulated in metabolic diseases and cancer. We discover here that in addition to its well characterized regulation by phosphorylation, PDH activity is also regulated via inhibitory oxidation of three cysteines of the DLAT subunit - Cys488, Cys586 and Cys618. Oxidation of these cysteines increases under oxidative stress, and is highly prevalent in mouse and human tissues. This mechanism enables cells to efficiently fight oxidative stress. Under oxidative stress, cells execute a metabolic shift, blocking glycolytic flux into the TCA cycle to shunt glycolytic carbons toward the pentose phosphate pathway. This generates NADPH which cells use to detoxify H2O2 and to reduce oxidized cysteines. We find that DLAT oxidation is required for cells to mount an effective antioxidant response. Mutations preventing DLAT oxidation render PDH resistant to oxidative inhibition, impair NADPH generation, reduce peroxide detoxification, and sensitize cells to oxidative damage and death. DLAT oxidation also drives a Warburg-like metabolic phenotype of increased glucose uptake, elevated lactate secretion, and reduced TCA cycle activity. Thus DLAT oxidation is a redox-sensing mechanism that regulates PDH activity and central carbon metabolism.

DOI: https://doi.org/10.1038/s41467-026-78266-6
Cancer Lett. 2026 Oct 13. pii: S0304-3835(26)00659-2. [Epub ahead of print] 218895

Acute MCL1 Loss via Homoharringtonine-Mediated Translational Inhibition Enables Potent Apoptotic Synergy with BCLXL Blockade.

Akira Ohtsu, Tatsuhiro Sawada, Larysa Poluben, Mai Onose, Hayumi Oyama, Ayaka Katayama, Fang Xie, Betul Ersoy-Fazlioglu, Juan M Jiménez-Vacas, Yusuke Otani, Yoshiyuki Miyazawa, Yoshitaka Sekine, Yuta Maeno, Takanori Shimizu, Tsukasa Oda, Shaoyong Chen, Olga Voznesensky, Xin Yuan, Luigi Giovanni Cecchi, Robert A Cerulli, Motohiro Izumi, Ikei S Kobayashi, Atsushi Tanaka, Nobuo Sasaki, Susumu S Kobayashi, Kazuhiro Suzuki, Steven P Balk, Seiji Arai.

Antiapoptotic buffering in solid tumors is generally mediated by both BCLXL and MCL1, so that BH3 mimetic drugs targeting only one have limited efficacy. To identify agents that may sensitize tumors to BH3 mimetics targeting BCLXL, we screened prostate cancer cells against a panel of mitochondria-targeted drugs in combination with navitoclax, a BH3 mimetic targeting BCL2 and BCLXL. Homoharringtonine (HHT) in combination with navitoclax and as a single agent emerged as a potent inducer of apoptosis. HHT has been identified as an inhibitor of protein translation, and proteomic analysis showed broad suppression of translation-related pathways, while immunoblotting demonstrated rapid decreases in short-lived proteins, including MCL1. HHT dose response and time course studies showed marked declines in MCL1 within 2 hours that were associated with apoptosis in response to BCLXL inhibition with navitoclax or A1331852. Further cell viability assays showed synergy between HHT and BCLXL inhibitors in multiple prostate, lung, and colorectal cancer cell lines. HHT monotherapy in vivo caused tumor regression in two prostate cancer xenograft models. Analysis of tumor tissue taken at 4 hours after dosing showed decreases in MCL1 and MYC, indicating that HHT levels obtainable in vivo are adequate to deplete short-lived proteins and potentially sensitize to BH3 mimetics targeting BCLXL. These findings support further exploration of HHT as a single agent in solid tumors and establish a rationale for investigating safer, tumor-selective approaches to combine HHT-mediated translational inhibition with BCLXL targeting.

DOI: https://doi.org/10.1016/j.canlet.2026.218895
Mol Ther. 2026 Oct 16. pii: S1525-0016(26)00872-5. [Epub ahead of print]

A natural compound derivative targeting HADHA disrupts mitochondrial homeostasis and suppresses renal cell carcinoma.

Ara Jo, Sanjeevram Dhandapani, Ziqin Wang, Hyeryeon Jung, Hongjun Jang, Morgan A Bailey, Andrew Tran, Brandon Tsai, Jinjae Park, Hyejin Lee, Hye-Jin Park, Yoojin Lim, Dolce Feenaghty, Victor M Moncada, Damu Wu, Keaton Chien, Nancy Chen, Yunsol Jo, Jiazheng Miao, Zhujun Yao, Jihoon Lee, Karthigayan Shanmugasundaram, Gang Greg Wang, Andrew Armstrong, Daniel George, David Howell, Jiaoti Huang, Michael C Fitzgerald, Jiyong Hong, Jung Wook Park.

Metastatic renal cell carcinoma (RCC) remains a lethal malignancy, and therapeutic resistance to current targeted and immune-based therapies highlights the need for new treatment strategies. Here, we identify C18-epi-brasilibactin A (CBA) as a selective inhibitor of RCC. High-throughput screening of a compound library derived from natural-products revealed that CBA potently suppresses RCC cell proliferation while sparing normal renal epithelial and liver cells. Mechanistically, CBA induces cell-cycle arrest, apoptosis, and DNA damage. Transcriptomic and functional analyses showed that CBA disrupts mitochondrial homeostasis by increasing mitochondrial mass and reactive oxygen species, indicating metabolic stress. Using proteomic approaches, we identified hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), a key enzyme in mitochondrial fatty acid β-oxidation, as a key functional mediator of CBA. Genetic depletion of HADHA phenocopied CBA effects, inducing ROS accumulation, DNA damage response, apoptosis, and growth inhibition in RCC cells. CBA treatment significantly suppressed RCC xenograft growth without systemic toxicity. Consistently, HADHA knockdown inhibited tumor progression, whereas HADHA overexpression enhanced tumor growth, supporting a tumor-supportive role for HADHA in RCC. Together, our findings identify HADHA-dependent mitochondrial metabolism as a functional vulnerability in RCC and establish CBA as a candidate therapeutic agent for targeting metabolic dependencies in metastatic renal cell carcinoma.

DOI: https://doi.org/10.1016/j.ymthe.2026.10.014