Targeting mitochondrial metabolism enhances radiosensitivity in DIPG and supports mitochondrial metabolism as a potential therapeutic weakness in this disease. Its effects are associated with reduced hypoxia-related signaling and broader metabolic and transcriptional changes.

To identify therapeutic interventions, we utilized drug response modeling and molecular docking, prioritizing RSL3, Atovaquone (targeting NOX4 (NADPH oxidase 4)/DHODH), and Sorafenib (targeting TrxR1 (thioredoxin reductase 1, encoded by TXNRD1)) as potent agents with potential ferroptosis-modulatory activity. Collectively, our findings demonstrate that NFE2L2-associated ferroptosis resistance shapes immune evasion in PRAD. Targeting ferroptosis regulators provides a compelling therapeutic rationale to remodel the TME and synergize with immune checkpoint blockade.

Therapeutically, combining the complex I inhibitor IACS-10759 with fulvestrant potently inhibited both tumor growth and metastasis. ICAM2⁺ cancer cells-enriched in treatment-resistant tumors-maintain elevated OXPHOS by assembling a functional complex with dynein and mitochondrial Complex I, thereby promoting mitochondrial trafficking. Disruption of this axis, either through ICAM2 depletion or Complex I inhibition, re-sensitizes tumors to therapy, revealing a targetable metabolic dependency in resistant disease.

Inhibiting TDP43 expression or using our newly identified TDP43 inhibitor, atovaquone, suppresses OXPHOS and reduces EGFR-TKI resistance. Overall, our research identified TDP43 as a key regulator of EGFR-TKI sensitivity and resistance, and offers new therapeutic targets and promising application perspectives in TNBC.

Treatment with the OXPHOS inhibitor IACS-010759 suppressed the proliferation, migration, invasion, and metastasis of RNF43-mutant tumors. Our findings identify a RNF43-YBX1-MYC signaling axis associated with metabolic reprogramming in pancreatic cancer and suggest that OXPHOS inhibition may represent a potential therapeutic vulnerability in tumors with RNF43-inactivating mutations.

Data from this study provides a mechanistic basis for PD-L1 elevation in tumors treated with atovaquone. Our studies support further development of atovaquone-anti-PD-L1 combination for the treatment of ovarian and other malignancies.

OxPhos inhibitor IACS-010759 demonstrated synergy with AZD4573 in vitro. Thus, CDK9 inhibition exhibits activity in ibrutinib-resistant MCL and can be further enhanced by co-targeting of OxPhos.

Furthermore, it predicted 51 candidate therapeutants, including atorvastatin, GSK-269962A, and atovaquone. These findings indicate that even in the absence of overt pathological stimulation, aortic tissue carrying the Myh11 K1256del variant exhibits a transcriptional program centered on ROCK signaling, which may prime the aorta for maladaptive responses to additional stress and may enhance susceptibility to dissection. This computational analysis requires experimental validation, but may provide a hypothesis-generating framework for development of preventive pharmacological interventions against FTAAD.

To address these challenges, we report a multifunctional nano-photosensitizer (TACR) constructed via a one-step self-assembly of a mitochondrial-targeting photosensitizer (TPP-Ppa), the hypoxia-relief agents (catalase and atovaquone), and a tumor-targeting ligand (RGD-PEG-BSA)...TACR-mediated photodynamic therapy induces immunogenic cell death and remodels the tumor microenvironment. In combination with α-PD-L1 immune checkpoint blockade, it elicits a systemic antitumor immune response, effectively suppressing both primary and distant tumors.

Our findings indicate that CRIP1 knockdown induces a glycolytic switch in AML cells, rendering them exquisitely sensitive to glycolytic inhibition by 2-DG. This suggests that CRIP1 status could serve as a biomarker for predicting response to metabolic therapies and highlights 2-DG as a promising therapeutic agent for a subset of AML characterized by glycolytic dependency.

The combination of anti-PD-L1 and paclitaxel (PTX) is a standard-of-care regimen for triple-negative breast cancer (TNBC)...This project aims to construct an albumin-based nanomedicine coloaded with atovaquone (ATO) and PTX for targeted tumor delivery, thereby enhancing the therapeutic efficacy of ICBs...This transformative approach significantly enhances the therapeutic efficacy of combination chemotherapy, leading to potent suppression of primary tumors while concurrently preventing postoperative recurrence and pulmonary metastases. This project has the potential to introduce innovative strategies and methodologies aimed at overcoming the limited efficacy of PTX combined with ICBs in the treatment of TNBC.

P1, N=26, Completed, Baylor College of Medicine | Active, not recruiting --> Completed