Abstract not available

CD97 (ADGRE5) is an adhesion GPCR (aGPCR) that plays crucial roles in the immune system and cancer. In this issue of Cell Chemical Biology, Wang et al.1 present the cryoEM structures of CD97 in complex with G13, Gq, and Gs G protein subtypes, revealing in-depth insight into aGPCR activation and G protein selectivity.

Genetics-based approaches can enable drug target identification in human cells. In this issue of Cell Chemical Biology, Nguyen et al.1 use inducible degradation of a mismatch repair protein to tune the mutation rate in HCT116 cells, thereby increasing sensitivity and selectivity in identifying resistance-conferring mutations for several cytotoxic small molecules.

The development of KRAS inhibitors was a remarkable feat, yet their efficacy is limited by inevitable resistance. In the September issue of Science, Lv et al.1 demonstrate how KRAS-driven cancers rewire signaling to restore protein homeostasis and acquire resistance to KRAS inhibitors with implications for novel combination therapeutic strategies.

Biofluid biomarkers to track neurodegenerative diseases in vitam are urgently needed. Recent studies1,2,3 show that large-scale proteomic analyses based on the proximity extension assay may reveal novel biomarkers reflecting disease pathophysiology. Such biomarkers will likely express their maximal clinical value when used in combination with pathology-specific biomarkers.

Protein quality control is often disrupted in heart diseases. In this issue of Cell Chemical Biology, Yang et al.1 describe the selective E3 ligase SPOP as a pro-fibrotic factor for inducing cardiac fibrosis through RACK1 degradation-mediated Smad3 activation.

Inhibitors for the KAT6 family of histone acetyltransferases (HATs) have been actively pursued due to the oncogenic roles of KAT6A in human cancer. CTx-648 is a novel KAT6A/B inhibitor with excellent pharmacokinetic properties and in vivo efficacy that represents a promising new treatment strategy for estrogen-receptor-positive breast cancer.

Serine/threonine protein phosphatases play a significant role in the survival and propagation of multiple cancers. In this issue of Cell Chemical Biology, Ahanin et al.1 demonstrate that protein phosphatase 5 (PP5) dephosphorylates and inactivates the cell death effector protein FADD independently of Hsp90, and they identify a selective PP5 inhibitor as a new therapeutic strategy for renal cancer.

Recent years have seen a remarkable growth in the field of protein-based medical treatments. Nevertheless, concerns have arisen regarding the cytotoxicity limitations, low affinity, potential immunogenicity, low stability, and challenges to modify these proteins. To overcome these obstacles, proximity-induced chemistry has emerged as a next-generation strategy for advancing protein therapeutics. This

Over the past decade or two, targeting metabolism has been effective in the treatment of many diseases and disorders, particularly cancer. In a metabolism focus issue in Cell Chemical Biology, this Voices piece asks researchers from a range of backgrounds: what are some major challenges and opportunities facing the field in the coming years?

Metabolic competition within the tumor microenvironment (TME) shapes the efficacy of anticancer immunity. In the August 3rd issue of Nature, Guo et al.1 show that glutamine is an intercellular metabolic checkpoint between cancer and immune cells. Targeting glutamine metabolism in the TME is a promising strategy to improve anti-cancer therapy.

Individuals with type 1 diabetes (T1D) have an increased risk of osteoporosis and fracture. In this issue of Cell Chemical Biology, Ji et al.1 show that impaired glucose metabolism in the bone-forming osteoblast drives diabetic osteoporosis in Akita mice, a mouse model of T1D.

MHC-II expression on cancer cells is associated with improved treatment outcome. In this issue, Huang et al.1 report a panel of small molecules that selectively upregulate MHC-II on cancer cells through suppression of fatty acid synthase (FASN), resulting in inhibition of tumor growth. Targeting this link between lipid metabolism and antigen presentation may improve response to immunotherapy.

The report of heightened lipid peroxidation has shone a spotlight on vulnerabilities within challenging cancers. In this context, FSP1 emerges as a pivotal regulator, actively countering the destructive effects of lipid peroxidation. In a groundbreaking development detailed in the latest issue of Cell Chemical Biology, Hendricks et al. unveil FSEN1, a potent inhibitor of FSP1. The discovery of FSEN1

T cells play a key role in driving autoimmunity, with alterations in metabolism powering their effector function. In the July 11 issue of Cell Metabolism, Jenkins et al.1 describe how a type 2 diabetes drug, canagliflozin, can be repurposed for the treatment of autoimmune disorders through metabolic reprogramming of the T cell response.