YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis.

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA-mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib-induced ferroptosis. Mechanistically, in a TEAD-dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib-induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovers a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ-based rewiring strategies as potential approaches to overcome HCC therapy resistance.

Natural α-methylenelactam analogues: Design, synthesis and evaluation of α-alkenyl-γ and δ-lactams as potential antifungal agents against Colletotrichum orbiculare.

In our continued efforts to improve the potential utility of the α-methylene-γ-lactone scaffold, 62 new and 59 known natural α-methylenelactam analogues including α-methylene-γ-lactams, α-arylidene-γ and δ-lactams, and 3-arylideneindolin-2-ones were synthesized as the bioisosteric analogues of the α-methylenelactone scaffold. The results of antifungal and cytotoxic activity indicated that among these derivatives compound (E)-1-(2, 6-dichlorobenzyl)-3-(2-fluorobenzylidene) pyrrolidin-2-one (Py51) possessed good selectivity with the highest antifungal activity against Colletotrichum orbiculare with IC50 = 10.4 µM but less cytotoxic activity with IC50 = 141.2 µM (against HepG2 cell line) and 161.2 µM (against human hepatic L02 cell line). Ultrastructural change studies performed by transmission electron microscope showed that Py51 could cause important cell morphological changes in C. orbiculare, such as plasma membrane detached from cell wall, cell wall thickening, mitochondria disruption, a dramatic increase in vacuolation, and eventually a complete loss in the integrity of organelles. Significantly, mitochondria appeared one of the primary targets, as confirmed by their remarkably aberrant morphological changes. Analysis of structure-activity relationships revealed that incorporation of the aryl group into the α-exo-methylene and the N-benzyl substitution increased the activity. Meanwhile, the α-arylidene-γ-lactams have superiority in selectivity over the 3-arylideneindolin-2-ones. Based on the results, the N-benzyl substituted α-(2-fluorophenyl)-γ-lactam was identified as the most promising natural-based scaffold for further discovering and developing improved crop-protection agents.