PDE3A-SLFN12 complex formation activates the SLFN12 RNase, but the biochemical details of RNase activation remain mysterious. In this issue of Cell Chemical Biology, Yan and colleagues report that two phosphoserines on SLFN12 are dephosphorylated in response to PDE3A binding, and this dephosphorylation is required for activation of the SLFN12 RNase.

In this issue of Cell Chemical Biology, Douglas et al. describe a potent, specific, and cell-permeable furin inhibitor that interacts with a cryptic binding site to rescue hallmarks of cystic fibrosis in human ex vivo models. BOS-318 holds promise for development of therapeutics targeting an array of furin-dependent pathologies.

Abstract not available

The molecular chaperone DnaK, is an attractive drug target for treating mycobacterial infections. In this issue, Hosfelt, Richards, and colleagues applied a high-throughput screen and discovered inhibitors that disrupt cofactor-mediated activation of DnaK. These inhibitors can lower bacterial survival under stress and decrease resistance to key antibiotics.

Accumulation of fat in the liver predisposes affected individuals to a variety of diseases, yet the molecular mechanisms leading to steatosis still remain elusive. Matsushita et al. (2022) propose a novel mechanism that interconnects insulin resistance and fatty liver formation by an orchestrated regulation of Irs2 and its natural antisense transcript.

In this issue of Cell Chemical Biology, Morgan et al. (2021) show that cyclic peptides can be potent and highly specific inhibitors for deubiquitinating enzymes. This study identifies the first selective inhibitors of the cancer-associated ubiquitin-specific protease 22 (USP22).

In this issue of Cell Chemical Biology, Olszewski et al. (2022) address the challenge of developing small molecules to inhibit glucose uptake in cancer. They characterize a novel pan-GLUT inhibitor that suppresses tumor growth and uncover how cancer cells can adapt to glucose restriction.

Preventing uncontrolled gene expression is a powerful therapeutic strategy for the treatment of cancers. In this issue of Cell Chemical Biology, Xu et al. (2022) describe a series of proteolysis targeting chimeras that induce the degradation of NSD3 and suppress cMyc-related oncogene transcription in a model of acute myeloid leukemia.

In this issue of Cell Chemical Biology, Palve et al. (2022) identified PARP16 as a non-canonical therapeutic target of the PARP1 inhibitor talazoparib, which synergizes with the WEE1 inhibitor adavosertib to enhance its efficacy. The dual targeting of PARP1 and PARP16 may explain the greater efficacy of talazoparib in some cancers.

Acetyl-coenzyme A is an important metabolite and regulates diverse cellular processes, including metabolism and epigenetics. In this issue of Cell Chemical Biology, Summers et al. (2022) describe an essential parasite enzyme, acetyl-coenzyme A synthetase, as a target of two antimalarial small molecules active against liver and blood stages of the parasite.

Ferroptosis is an iron-dependent form of cell death implicated in cancer and neurodegenerative diseases. In this issue of Cell Chemical Biology, Shao et al. (2022) and Wang et al. (2022) describe imaging techniques to monitor ferrous iron levels and iron-dependent lipid peroxidation, two key determinants of ferroptosis sensitivity.

Appropriately responding and adapting to genotoxic, oxidative, and metabolic stress is essential for survival and is at the heart of maintaining homeostasis. In this issue of Cell Chemical Biology, Jiang et al. (2021) describe an autophagy-dependent mechanism for cytoprotective H2S generation initiated by DNA damage and other small molecule treatments.