Proteolysis limits the therapeutic use of peptide antibiotics. Wang et al. develop C12RP7, a fatty-acid-modified Arg-Pro lipopeptide that resists proteases, kills antibiotic-resistant bacteria, shows low toxicity and resistance propensity, and provides oral efficacy through bacterial membrane disruption and host metabolic modulation.

Post-translational modifications (PTMs) generate protein structure and function diversity. Advances in mass spectrometry have revealed numerous bacterial PTMs, increasing the need to understand their functional purpose. Dale et al. review these modifications and examine their evolving roles in bacterial physiology and pathogenesis.

Integrin inhibitors are drugs designed to block cell adhesion, but they have repeatedly failed in clinical trials. Lee et al. show that these drugs cannot inhibit a newly discovered adhesion structure, curved adhesions, and therefore fail to block cancer cell invasion in 3D, potentially explaining some previous clinical failures.

Wang et al. herein review recent progress in the systematic identification of post-translational modifications and non-covalent interactions mediated by the immunomodulatory metabolite itaconate using chemoproteomic methods. These studies have provided rich resources to guide future functional studies to better understand the multiple roles of itaconate in host-pathogen interactions.

Using proximity labeling, Barresi et al. defined the MuSK signaling network at the neuromuscular junction (NMJ) and identified 74 associated proteins. Crk-L emerged as an early signaling hub, while Rapgef1 was revealed as a critical downstream effector required for AChR clustering and NMJ stability.

Mathiasen et al. provide a diffusion-based single-molecule approach for studying how G protein-coupled receptors engage G proteins in living cells. Native interactions are not resolved at 15 ms, but a nucleotide-decoupled Gαi1 4A mutant shows that agonist increases the rate of receptor engagement without altering complex lifetime, consistent with efficacy being reflected in engagement probability.

(Cell Chemical Biology 33, ▪▪–▪▪.e1–e6, December 17, 2026)

Gudauskaitė et al. show that the mechanism driving oncogenic protein overexpression influences the effectiveness of targeted protein degradation. While stabilizing mutations do not limit protein depletion, increased protein production limits how far degraders can reduce target levels, with implications for cancer therapy and drug resistance.

Park et al. describe a high precision, small molecule tool patterned after a natural toxin for acute, selective, and reversible inhibition of an engineered voltage-gated sodium channel. By combining chemistry and genetics, this technology enables physiological studies of any one of six NaV subtypes (NaV1.1–1.4, 1.6, 1.7).

Seo et al. develop APEX-RNA-MS, a strategy integrating proximity labeling and nucleoside mass spectrometry, to characterize the spatial distribution of modified RNAs within human cells. They profile RNA modifications proximal to the proteins found in non-membrane-bound cellular structures, including stress granules, P-bodies, and DNA damage foci.

Rouhimoghadam et al. demonstrate that single-atom chemical edits can reprogram E3 ligase selection by molecular glue degraders. By revealing that only specific ternary complex geometries drive ubiquitination, this work establishes a mechanistic framework for designing tunable, ligase-switchable degraders.

Lindquist et al. show that GLP-1 and semaglutide, but not exendin 4 or GIP, selectively drive GLP-1R-GIPR heterodimerization, altering receptor trafficking and signaling. These findings uncover a mechanistic basis for incretin crosstalk and provide a structural framework for optimizing therapies for obesity and type 2 diabetes.

Ma et al. develop a dual-function PROTAC that degrades ACSL4 to reduce PUFA-containing membrane phospholipids while activating the PPARγ antioxidant pathway to enhance cellular antioxidant defense. Brain-targeted delivery of dACSL4 via biodegradable lipid nanoparticles effectively suppresses neuronal ferroptosis, reducing dopaminergic neuron loss and improving motor function in Parkinson’s disease models.

Endogenous mechanisms that restrain inflammation remain incompletely understood. Colussi et al. identify membrane phospholipids as reservoirs of endogenous nitrated fatty acids that are rapidly mobilized during inflammatory stress. Release of NO2-CLA suppresses inflammatory signaling and preserves vascular homeostasis, revealing a previously unrecognized anti-inflammatory reserve that becomes depleted during disease.

Shao et al. identified NAT10-mediated RNA acetylation as a key epitranscriptomic regulator of atopic dermatitis. NAT10 stabilized RELB mRNA to coordinate a pro-inflammatory checkpoint in keratinocytes that drove neutrophil recruitment. Targeting NAT10/ac4C axis with Remodelin offers a potent chemical strategy for treating inflammatory skin diseases.

Atopic dermatitis (AD) is driven by complex interactions between keratinocytes and immune cells. In this issue of Cell Chemical Biology, Shao et al. identify that NAT10-dependent ac4C modification stabilizes Relb mRNA in keratinocytes, promoting chemokine production, neutrophil recruitment, and dermatitis progression.

Excessive and sustained neuroinflammation can cause neuronal damage. Wang et al. show that neuronal glycoRNAs bind Siglec-11 on immune cells, suppressing NF-κB and inflammatory cytokines and protecting neurons.

Cell-surface glycoRNAs are emerging as neuroimmune signals. In this issue of Cell Chemical Biology, Wang et al. showed in co-culture that neuronal glycoRNAs engaged microglial Siglec-11, increased SHP1 phosphorylation, suppressed NF-κB-dependent cytokine production, and improved neuronal-cell survival, establishing signaling direction, downstream mechanism, and protective function for a glycoRNA-Siglec pathway.

Gao et al. identify RBBP7 as a rapamycin target that regulates histone H4 acetylation. Guided by this mechanism, they develop RBBP7-targeting peptides that suppress tumor growth and enhance the activity of HDAC inhibitors in liver cancer models.

Neurons rely on local translational control to rapidly adapt protein synthesis across their complex architecture. Fischbach and Grosshans et al. highlight how the integrated stress response maintains neuronal homeostasis during physiological stress but drives dysfunction when chronically activated in infections, neuroinflammation, and neurodegenerative diseases.

Li et al. identify DPP3 as a natural brake on the non-canonical inflammasome. DPP3 cleaves PEBP1 to produce a fragment that directly inhibits caspase-4/11. Zinc chelators block DPP3 to potentiate inflammation, whereas promoting DPP3 activity improves sepsis survival, highlighting a potential therapeutic strategy.

Histone deacetylases regulate epigenetic signaling and diverse lysine acyl modifications, making them attractive therapeutic targets. Rogers and Olsen review how peptide-based technologies have uncovered HDAC function and specificity and discuss emerging platforms for profiling enzymes and discovering inhibitors.

Xu et al. introduce OGTAC, a chemically induced proximity strategy that recruits O-GlcNAc transferase to c-Myc to achieve targeted post-translational modification (PTM) rather than degradation. The study establishes PTM editing as an approach for rewiring transcription factor activity.

Gudauskaitė et al. show that the mechanism driving oncogenic protein overexpression influences the effectiveness of targeted protein degradation. While stabilizing mutations do not limit protein depletion, increased protein production limits how far degraders can reduce target levels, with implications for cancer therapy and drug resistance.

Park et al. describe a high precision, small molecule tool patterned after a natural toxin for acute, selective, and reversible inhibition of an engineered voltage-gated sodium channel. By combining chemistry and genetics, this technology enables physiological studies of any one of six NaV subtypes (NaV1.1–1.4, 1.6, 1.7).

Cysteine reactivity profiling helps identify functionally important and potentially druggable cysteines. Schaffer et al. show that PMSF and orthovanadate generate a lysis-derived oxidant that reveals a functionally important cysteine in NAGK and provides a complementary strategy for profiling cysteine engagement.

Ischemia-reperfusion injury lacks effective therapies because inflammatory and cell death pathways act in concert. Yin et al. reveal that the STING inhibitor H-151 also functions as a radical-trapping antioxidant, enabling dual inhibition of STING signaling and ferroptosis to protect against renal ischemia-reperfusion injury.

Expanding the therapeutic scope of highly specific proteases requires reliable strategies for altering substrate recognition. Garrido et al. establish a comparative protein engineering approach that redirects botulinum neurotoxin proteases to new SNARE substrates, yielding an LC/E variant with >26,000-fold enhanced SNAP29 cleavage and undetectable activity toward its native substrate.

Spatiotemporal manipulation of neural circuits relies on genetic tools which require recombinant expression of exogenous actuators. Bátora et al. show that localized covalent inhibition of endogenous NMDA receptors is sufficient to reprogram behavior. Their two-photon molecular tattooing approach enables persistent, region-specific modulation of neural circuits without genetic manipulation.

Wang et al. repurpose the XPO1 inhibitor selinexor for hepatocellular carcinoma through an integrated mechanistic and therapeutic study. The work uncovers an NCOR1/FOXK1-driven oxidative stress pathway, identifies the KEAP1-NRF2 axis as a predictive biomarker, and reveals a synergistic combination strategy with disulfiram.

Proteostasis pathways offer opportunities for engineering cellular control systems. Ogurlu et al. repurpose IRE1α-dependent XBP1 splicing to create RNA rheostats that link ER stress sensing with transgene expression, establishing a feedback mechanism that limits protein overexpression and improves control of gene and mRNA therapies.

Zhang et al. describe ZH-1a, a high-affinity DNA aptamer that preferentially targets the HMGB1 B-box domain. By neutralizing extracellular HMGB1, ZH-1a suppresses inflammatory signaling, protects against acute inflammatory injury and polymicrobial sepsis, and enhances methotrexate efficacy in an arthritis model.

SFPQ regulates extra-long genes critical for neuronal development and function. Using super-resolution imaging and SFPQ-focused BioID, Hosokawa et al. identify RNA-dependent meshwork condensates that act as transcriptional elongation hubs. These structures coordinate splicing, elongation, and chromatin regulation, revealing a multidimensional regulatory network whose disruption is linked to neurological disease.

Protective epitopes on the EBV fusion apparatus remain incompletely defined. Zhao et al. identify 4G12, a human antibody targeting a quaternary epitope on the gHgL-gp42 complex that neutralizes infection and protects humanized mice, revealing a vulnerable site for vaccine design.

Ryan and Zanoni redefine TCA cycle metabolites as metabolic danger signals that shape immunity across infections, inflammation, and cancers. They introduce the concept of metabolic DAMPs (“metaDAMPs”) as a unifying framework for understanding immune activities of endogenous metabolites and outline emerging technologies positioning immunometabolism as a tractable axis for therapeutic intervention.

In a recent issue of Molecular Cell, Ramage et al. identify a Cullin-RING E3 ubiquitin ligase complex defined by the substrate adaptor LRRC58 that inversely regulates the abundance of LRRC58 and its cognate substrate, CDO1, in response to cysteine levels.

Chandra et al. leverage a human dual-cell model of FA and discover cell-type-specific vulnerabilities to frataxin deficiency. A Miro1-binding probe, MR3, modulates FA cell-type-unique molecular signatures and alleviates mitochondrial damage via potential allosteric reshaping of Miro1 protein. Previously unreported Miro1 ligands expand MR3 chemical diversity.

In this issue of Cell Chemical Biology, Chandra and colleagues demonstrate that allosteric modulation of the mitochondrial protein Miro1 can selectively reprogram mitochondrial stress signaling. Chemical targeting of a single molecular hub can produce distinct responses in disease-relevant cell types, despite acting within a broadly conserved stress pathway.

Cell fate decisions after genotoxic stress are critical determinants of therapeutic outcome. Gallagher Aldave et al. identify the BAX/BAK apoptotic checkpoint as a key regulator of entry to therapy-induced senescence and show that senescent cells acquire vulnerabilities to Bcl-xL and Mcl-1 targeting that can be leveraged to promote apoptosis.

Genotoxic drugs induce apoptosis-resistant senescent “zombie” cells. In this issue of Cell Chemical Biology, Gallagher Aldave et al. show that these cells acquire dependence on BCL-xL and MCL-1, creating a therapeutic vulnerability to their inhibitors and degraders.

Neuroinflammation is a major secondary driver of Alzheimer’s disease (AD). In this issue of Cell Chemical Biology, Carnevale et al. demonstrate that S-nitrosylation of the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway sustains pathological neuroinflammation in AD, identifying a promising therapeutic target for this devastating disease.

Carnevale et al. demonstrate that S-nitrosylation of human STING at cysteine 148 drives microglial inflammation and synaptic dysfunction in Alzheimer’s disease. This study uncovers a redox-sensitive mechanism linking nitrosative stress to innate immunity and identifies SNO-STING as a potential therapeutic target for neurodegenerative disorders and other conditions with hyperactive STING signaling.

Targeted cancer therapies most commonly block hyperactive signaling pathways that drive transformation. Kretschmer and Mitchell et al. instead describe a strategy to enhance signaling by a tumor suppressor kinase through the targeting of an interacting protein that binds to but does not metabolize ATP illustrating an alternative approach to targeting cancer.

Lysine acylation is emerging as a fundamental mechanism linking cellular metabolism to protein regulation. Hintzen and Burslem synthesize the chemical biology, mechanistic principles, and unresolved questions that are redefining lysine acylation from an expanding catalog of modifications into a unifying framework for understanding metabolic regulation while outlining challenges.

Edoo et al. identify BVL3572S, a hydroxamic acid-containing compound that inhibits Mycobacterium tuberculosis growth. BVL3572S targets the pyridoxal phosphate (PLP)-dependent aminotransferases HisC and AlaA, blocking L-histidine and L-alanine biosynthesis and broadly impacting bacterial metabolism. BVL3572S synergizes with the second-line antibiotic D-cycloserine.

Glucocerebrosidase (GCase) has been implicated in Parkinson’s disease, but unraveling its role is hampered by a lack of selective chemical tools. Wang et al. develop chemical tools that enable selective inactivation and monitoring of GCase in vitro and in vivo, facilitating studies of disease mechanisms and efficacy of GCase-targeting therapies.

Proteostasis pathways offer opportunities for engineering cellular control systems. Ogurlu et al. repurpose IRE1α-dependent XBP1 splicing to create RNA rheostats that link ER stress sensing with transgene expression, establishing a feedback mechanism that limits protein overexpression and improves control of gene and mRNA therapies.