Protein palmitoylation is an important lipidic post-translation modification catalyzed by the zDHHC protein acyltransferases. In this issue of Cell Ch…

ABHD17C-mediated depalmitoylation of BCL6B at Cys442 blocks its nuclear import and triggers ubiquitin-dependent degradation, attenuating transcriptional repression of the anti-phagocytic signal CD24.....

Accurate S-palmitoylation detection at cellular and tissue levels remains challenging. Zhang et al. develop PALM-Scan, a nanopore platform that directly reads S-palmitoylation on peptides. This label-free method monitors depalmitoylation kinetics in real time, distinguishes competing cysteine modifications, and detects palmitoylated disease biomarkers from serum samples, thereby providing a transformative tool for studying protein S-palmitoylation in health and disease.

Accurate S-palmitoylation detection at cellular and tissue levels remains challenging. Zhang et al. develop PALM-Scan, a nanopore platform that directly reads S-palmitoylation on peptides. This label-free method monitors depalmitoylation kinetics in real time, distinguishes competing cysteine modifications, and detects palmitoylated disease biomarkers from serum samples, thereby providing a transformative tool for studying protein S-palmitoylation in health and disease.

Abstract. Pheomelanin is a sulfur-containing pigment produced by melanocytes notably in individuals with red hair/fair skin and animals with orange integum

A single-cell atlas of pancreatic ductal adenocarcinoma development reveals progressive ductal-fibroblast-immune crosstalk. Tumor-derived LAMB3 drives the formation of immunosuppressive LRRC15+ fibro...

HCV infection poses a significant global health burden. Despite the remarkable efficacy of direct antiviral agents, developing new strategies targeting host factors is crucial for addressing drug resi...

The palmitoylation/depalmitoylation cycle regulates protein localization, function, and stability, playing essential roles in signal transduction, membrane trafficking, and neuronal activity. Understanding the enzymes involved may reveal novel therapeutic targets. Palmitoyl-protein thioesterase-1 (PPT1) is a key depalmitoylase that removes palmitate from target proteins. Deficiency in PPT1 causes Batten disease (CLN1), a fatal neurodegenerative disorder, while overexpression has been linked to various cancers. Emerging evidence also implicates PPT1 in other neurodegenerative, autoimmune, and reproductive diseases. Recognizing its broad biological significance, PPT1 is an enzyme with growing therapeutic interest; however, translational hurdles still remain. This review provides an overview of PPT1 structure, enzymatic activity, substrates, and roles across systems, alongside a landscape of PPT1-targeted drugs in preclinical and clinical development that will inform future research.

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Phosphorylation of ABHD17C induced by KRAS mut /ERK signaling facilitates ALOX15B depalmitoylation and degradation via the CUL4/DDB1/DCAF10 complex, thereby enabling KRAS mut -PDAC cell to evade ferroptosis. Methyl protodioscin inhibits KRAS mut -PDAC progression by disrupting the ABHD17C/ALOX15B interaction and inducing ferroptosis, which represents a potential therapeutic strategy for KRAS mut -PDAC. Abstract Understanding the mechanisms underlying Kirsten rat sarcoma (KRAS) mutation-driven development and progression of pancreatic ductal adenocarcinoma (PDAC) may facilitate the discovery of novel strategies for KRAS-mutant PDAC (KRAS mut -PDAC) treatment. Here, it is reported that downregulation of arachidonate 15-lipoxygenase (ALOX15B) significantly correlated with poor outcomes in patients with KRAS mut -PDAC. Mechanistically, KRAS mut /ERK1-elicited phosphorylation of ABHD17C promotes depalmitoylation and membrane-to–cytoplasm translocation of ALOX15B, facilitating proteasome-dependent degradation of ALOX15B via interaction with the E3 ligase complex CUL4/DDB1/DCAF10. Notably, treatment with methyl protodioscin (MPD), a steroid saponin primarily purified from polygonatum sibiricum rhizome, restored the S-palmitoylation and membrane location of ALOX15B via disruption of the ABHD17C/ALOX15B interaction, consequently resulting in significant inhibition of growth rate of patient-derived KRAS mut -PDAC organoids in vitro and KRAS mut -PDAC-formed tumor in vivo via induction of ferroptosis. Therefore, these findings unveil a prominent role of ferroptosis evasion in KRAS mut -PDAC progression and highlight the potential of targeting KRAS/ERK1/ABHD17C/ALOX15B axis in KRAS mut -PDAC treatment.

Abstract. Pheomelanin is a sulfur-containing pigment produced by melanocytes notably in individuals with red hair/fair skin and animals with orange integum