To overcome this, we screened various metalloporphyrins and identified Cu-based verteporfin as an effective YAP inhibitor, so that a tumor-targeted nanosystem termed CuVP-F127-IKE-Mem is developed, which integrates the YAP inhibitor copper-verteporfin metalloporphyrin and the ferroptosis inducer imidazole ketone erastin (IKE) into cancer cell membrane-coated nanoparticles. In pancreatic cancer, CuVP-F127-IKE-Mem significantly enhances ferroptosis sensitivity, suppresses YAP/SLC7A11 signaling, and exhibits potent tumor growth inhibition in vivo. This YAP-targeted transcriptional regulation strategy establishes a new paradigm for overcoming ferroptosis resistance.

In this study, we designed and synthesized Photodegradation-Targeting Chimeras (PDTACs) by conjugating a clinically approved photosensitizer, verteporfin, to a PD-L1-targeted peptide...In mouse models with immune cold tumors, PPA-VPF elicited robust adaptive antitumor immunity and effectively inhibited the growth of both primary and distant tumors. This PD-L1-targeted PDTAC achieved immune checkpoint blockade and ICD induction in a single therapeutic mode using one molecular species, presenting a novel strategy for combinational immunotherapy, particularly in immune cold tumors.

P1, N=5, Terminated, Roswell Park Cancer Institute | Active, not recruiting --> Terminated; low accrual

YAP1 and tumor-like CAFs (tCAFs) play a pivotal role in driving desmoplasia in PDAC. YAP1 mediates the conversion of mCAFs to tCAFs and remodels the extracellular matrix (ECM), while high YAP1 activity in tCAFs regulates EMT induction to propel disease progression. Targeting the YAP1-tCAF axis can suppress desmoplasia and improve therapeutic outcomes. Magnetic resonance elastography (MRE) holds significant potential for non-invasive monitoring of stromal mechanics, offering a new perspective for stromal therapies in PDAC.

In this study, elesclomol (ES) or disulfiram (DSF)/Cu was used to induce cuproptosis, and bathocuproine disulfonic acid (BCS) was used to inhibit it. In vivo, the role of the ALKBH5-ATOX1 axis in AML progression has also been confirmed. In Conclusion, The demethylase ALKBH5 downregulates ATOX1 by reducing its m⁶A levels, thereby modulating cuproptosis in AML-a mechanism that offers potential novel insights and therapeutic targets for AML treatment.

Using CRISPR/Cas9-mediated knockout and rescue experiments in EOC cell lines, we demonstrate that MED12 deficiency significantly enhances sensitivity to ferroptosis inducers (RSL3 and Erastin), as evidenced by reduced IC50 values...Pharmacological inhibition of YAP with verteporfin or siRNA-mediated TEAD1 knockdown reverses ferroptosis sensitivity in MED12-deficient cells, confirming pathway specificity. These findings establish MED12 as a modulator of the YAP-TEAD1-ferroptosis axis and suggest that targeting this pathway could overcome chemoresistance in MED12-deficient EOC. Our work provides a mechanistic foundation for exploiting ferroptosis induction as a therapeutic strategy in ovarian cancer.

Next, two gastric cancer cell lines (AGS, HGC27) were selected for in vitro experiments to assess the combined effects of PUN and the copper ionophore elesclomol (ES) (hereafter referred to as ES-Cu, representing the combination of ES and Cu2+)...In combination therapy strategies, PUN can work synergistically with chemotherapy drugs to suppress gastric cancer growth. Furthermore, PUN enhances its inhibitory effect on gastric cancer by working synergistically with cuproptosis through targeting FDX1.

P=N/A, N=100, Not yet recruiting, Aura Biosciences

SLC7A11 knockdown regulates intracellular redox balance through the GSH-GPX4 axis, thereby promoting cellular cuproptosis. Targeting SLC7A11 can enhance the sensitivity of CRC cells to copper ionophores and may represent a novel therapeutic strategy to enhance cuproptosis of CRC cells.

In contrast, co-treatment with Cu and copper ionophore elesclomol (Cu-ES) triggered cuproptosis, a unique copper-dependent form of cell death, accompanied by mitochondrial dysfunction, dihydrolipoamide S-acetyltransferase aggregation, and ATP depletion. The PLK1 inhibitor BI-2536 recapitulated the effects of Cu-ES and exhibited synergistic activity when combined with Cu-ES, enhancing both cell death and EMT suppression. These findings highlight a novel regulatory mechanism of EMT through copper signaling and support copper-based combination therapies as a promising approach to simultaneously inhibit tumor growth and metastasis in colorectal cancer.

This inhibition collectively diminishes the expression and activity changes in complex IV, induces mitochondrial dysfunction, and promotes cuproptosis in ovarian cancer. This study further demonstrates that inhibiting the oxidative phosphorylation complex IV can enhance copper-induced cell death in ovarian cancer.

Importantly, two clinical drugs, the RhoA inhibitor simvastatin and the YAP1/TEAD inhibitor verteporfin were determined to be the disruptors of this feed-forward signaling axis, inhibiting ICC tumor growth. These findings reveal the vital function of ANLN in ICC growth and provide promising treatment strategies for ICC.