The unfolded protein response (UPR) is a cellular homeostatic mechanism that is activated in many human cancers and plays pivotal roles in tumor progression and therapy resistance. However, the molecular mechanisms for UPR activation and regulation in cancer cells remain elusive. Here, we show that oncogenic MYC regulates the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) branch of the UPR in breast cancer via multiple mechanisms. We found that MYC directly controls IRE1 transcription by binding to its promoter and enhancer. Furthermore, MYC forms a transcriptional complex with XBP1, a target of IRE1, and enhances its transcriptional activity. Importantly, we demonstrate that XBP1 is a synthetic lethal partner of MYC. Silencing of XBP1 selectively blocked the growth of MYC-hyperactivated cells. Pharmacological inhibition of IRE1 RNase activity with small molecule inhibitor 8866 selectively restrained the MYC-overexpressing tumor growth in vivo in a cohort of preclinical patient-derived xenograft models and genetically engineered mouse models. Strikingly, 8866 substantially enhanced the efficacy of docetaxel chemotherapy, resulting in rapid regression of MYC-overexpressing tumors. Collectively, these data establish the synthetic lethal interaction of the IRE1/XBP1 pathway with MYC hyperactivation and provide a potential therapy for MYC-driven human breast cancers.

Glutathione plays many important roles in biological processes; however, the dynamic changes of glutathione concentrations in living cells remain largely unknown. Here, we report a reversible reaction-based fluorescent probe—designated as RealThiol (RT)—that can quantitatively monitor the real-time glutathione dynamics in living cells. Using RT, we observe enhanced antioxidant capability of activated neurons and dynamic glutathione changes during ferroptosis. RT is thus a versatile tool that can be used for both confocal microscopy and flow cytometry based high-throughput quantification of glutathione levels in single cells. We envision that this new glutathione probe will enable opportunities to study glutathione dynamics and transportation and expand our understanding of the physiological and pathological roles of glutathione in living cells.

Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton’s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.

Kidney injury initiates metabolic reprogramming in tubule cells that contributes to the development of chronic kidney disease (CKD). Exercise has been associated with beneficial effects in patients with CKD. Here we show that the induction of a myokine, irisin, improves kidney energy metabolism and prevents kidney damage. In response to kidney injury, mice with muscle-specific PGC-1α overexpression (mPGC-1α) exhibit reduced kidney damage and fibrosis. Metabolomics analysis reveals increased ATP production and improved energy metabolism in injured kidneys from mPGC-1α mice. We identify irisin as a serum factor that mediates these metabolic effects during progressive kidney injury by inhibiting TGF-β type 1 receptor. Irisin depletion from serum blunts the induction of oxygen consumption rate observed in tubule cells treated with mPGC-1α serum. In mice, recombinant irisin administration attenuates kidney damage and fibrosis and improves kidney functions. We suggest that myokine-mediated muscle-kidney crosstalk can suppress metabolic reprograming and fibrogenesis during kidney disease.

Rifampicin and isoniazid are often used together as a co-therapy to treat tuberculosis, but their combined use often leads to hepatoxicity in humans. Xiaochao Ma and colleagues now report the mechanisms behind this side effect, thus opening a possible avenue to the safer use of these effective drugs. Co-therapy with rifampicin (RIF) and isoniazid (INH) used to treat tuberculosis in humans frequently causes liver injury. Here, using a pregnane X receptor (PXR)-humanized mouse model, we found that co-treatment with RIF and INH causes accumulation of the endogenous hepatotoxin protoporphyrin IX in the liver through PXR-mediated alteration of the heme biosynthesis pathway. These results provide insight into the mechanism of liver injury induced by co-treatment with these compounds and may lead to their safer use in the clinic.