Feng et al. developed an inclusion-complex-enhanced nano-micelle formulation of CBD (CBD-IN) that enhances brain delivery and rapidly suppresses neuropathic pain in mice without affecting normal function. Circuit mapping and calcium imaging reveal state-dependent suppression of pathological hyperactivity, highlighting CBD-IN as a promising therapeutic strategy.

Wang et al. engineered D2HG biosensors (DHsers) leveraging insights from structural mechanism of D2HG regulation of DhdR, achieving varying detection ranges. The DHsers enable the detection of D2HG dynamics in healthy cells and disease-relevant IDH mutant living cells, providing a valuable tool for quantifying subcellular D2HG levels.

Abrams et al. used circular permutation to develop a reversible FRET-based cysteine sensor. Biochemical and cell-based experiments established the sensor’s sensitivity and selectivity for cysteine. High-throughput phenotypic screens identified compounds that modulate cysteine levels, establishing the sensor as a valuable tool for studying cellular cysteine regulation.

Based on an acute exercise model, Yan et al. identify lactate as a positive regulator of autophagy in skeletal muscle. Lactate triggers muscle autophagy via K921 lactylation-dependent inactivation of mTORC1. This study establishes a mechanistic framework for understanding exercise-induced muscle adaptation, guiding treatment strategies for muscle and metabolic disorders.

Yuan et al. identify TRIM28 as a key component of stress granules (SGs) using the lcFAX-MS approach established here and define TRIM28-mediated G3BP1/2 SUMOylation as a critical mechanism regulating SG dynamics. TRIM28’s role in regulating SGs, facilitated by lcFAX-MS, provides a promising framework for studying diverse LLPS events.

Phenotypic drug discovery is a powerful tool for uncovering new therapies, but small molecule and genetic screens each have distinct limitations. Vincent and Gianni analyze these challenges and suggest practical mitigation strategies to maximize screening success.

Loss of RNF43 leads to aberrant Wnt signaling, promoting aggressive cancers for which effective treatments are lacking. He et al. demonstrate that STT3A is critical for the survival of RNF43-deficient tumors, identifying it as a promising therapeutic target validated through both in vitro and in vivo studies.

Aberrant Wnt signaling activation occurs in various cancers but has limited druggable targets. In this issue of Cell Chemical Biology, He et al. established a double death trap Wnt reporter system. Combined with genome-wide CRISPR screening, this approach identified STT3A as an essential Wnt signaling regulator with therapeutic potential.

Targeting the WDR5-MLL1 interaction offers a promising therapeutic strategy for leukemia. Zhang et al. developed Ac7, an EMBOW-derived peptide that binds WDR5 with nanomolar affinity, disrupts the WDR5-MLL1 interaction, and suppresses leukemia cell growth in vivo with relatively low toxicity.

In this issue of Cell Chemical Biology, Zhang et al. report the identification of a high-affinity EMBOW-derived inhibitor of WDR5, Ac7, which demonstrates in-cell target engagement and in vivo antileukemic efficacy. The microprotein-inspired inhibitor potently blocks the WDR5-MLL1 interaction, suppressing H3K4 methylation and transcription of target genes in mixed lineage leukemia (MLL)-rearranged leukemia.

In an interview with Dr. Mishtu Dey, the editor-in-chief of Cell Chemical Biology, the authors of the research article entitled “TRIM28-mediated SUMOylation of G3BP1/2 regulates stress granule dynamics” share insights about their work and reflect on their scientific field and their journeys as researchers.

Li et al. demonstrated that phytate confers radioprotective effects by promoting colonization of symbiotic Parasutterella, which produce the metabolites PLA and NL. These metabolites help mitigate radiation-induced intestinal injury (RIII) via M2-like macrophage polarization and antioxidant activity, highlighting phytate’s potential benefits for cancer patients undergoing radiotherapy without increasing gut burden.

Phenotypic drug discovery is a powerful tool for uncovering new therapies, but small molecule and genetic screens each have distinct limitations. Vincent and Gianni analyze these challenges and suggest practical mitigation strategies to maximize screening success.

Based on an acute exercise model, Yan et al. identify lactate as a positive regulator of autophagy in skeletal muscle. Lactate triggers muscle autophagy via K921 lactylation-dependent inactivation of mTORC1. This study establishes a mechanistic framework for understanding exercise-induced muscle adaptation, guiding treatment strategies for muscle and metabolic disorders.

Abrams et al. used circular permutation to develop a reversible FRET-based cysteine sensor. Biochemical and cell-based experiments established the sensor’s sensitivity and selectivity for cysteine. High-throughput phenotypic screens identified compounds that modulate cysteine levels, establishing the sensor as a valuable tool for studying cellular cysteine regulation.

Feng et al. developed an inclusion-complex-enhanced nano-micelle formulation of CBD (CBD-IN) that enhances brain delivery and rapidly suppresses neuropathic pain in mice without affecting normal function. Circuit mapping and calcium imaging reveal state-dependent suppression of pathological hyperactivity, highlighting CBD-IN as a promising therapeutic strategy.

Wang et al. engineered D2HG biosensors (DHsers) leveraging insights from structural mechanism of D2HG regulation of DhdR, achieving varying detection ranges. The DHsers enable the detection of D2HG dynamics in healthy cells and disease-relevant IDH mutant living cells, providing a valuable tool for quantifying subcellular D2HG levels.

Yuan et al. identify TRIM28 as a key component of stress granules (SGs) using the lcFAX-MS approach established here and define TRIM28-mediated G3BP1/2 SUMOylation as a critical mechanism regulating SG dynamics. TRIM28’s role in regulating SGs, facilitated by lcFAX-MS, provides a promising framework for studying diverse LLPS events.

Targeting the WDR5-MLL1 interaction offers a promising therapeutic strategy for leukemia. Zhang et al. developed Ac7, an EMBOW-derived peptide that binds WDR5 with nanomolar affinity, disrupts the WDR5-MLL1 interaction, and suppresses leukemia cell growth in vivo with relatively low toxicity.

Loss of RNF43 leads to aberrant Wnt signaling, promoting aggressive cancers for which effective treatments are lacking. He et al. demonstrate that STT3A is critical for the survival of RNF43-deficient tumors, identifying it as a promising therapeutic target validated through both in vitro and in vivo studies.