ASS1 (Argininosuccinate synthase 1)

Autophagy was shown to induce cell death since its inhibition using chloroquine (CQ) significantly decreased [HuArgI (Co)-PEG5000]-induced cytotoxicity, indicating autophagic cell death in AML cells following arginine deprivation. Moreover, we showed that arginine deprivation leads to ROS accumulation and that neutralizing ROS using N-acetylcysteine (NAC) does not affect the autophagic response but completely reverses the cytotoxicity of arginine deprivation, demonstrating that death by autophagy is dependent on ROS generation in AML cells.

ATF4 knockout in melanoma cells phenocopied ASS1 knockout in the same cells, both showing greater sensitivity to arginine depletors such as ADI-PEG20...Single cell transcriptomics profiled the reshaped tumor microenvironment and revealed that a subset of resident macrophages were reprogrammed by endogenous arginine blockade. Overall, our findings reveal that the MYC-ATF4-ASS1 axis not only controls arginine vulnerability of melanomas but also shapes the immune microenvironment.

The cytochrome P450 enzymes CYP4A11 and CYP2C8 (lipid metabolism), the amino-acid metabolism enzymes ASS1 and FAH, and the carbohydrate metabolism enzymes ALDOB and GAPDH were identified as key regulatory proteins in HCC progression. Aberrant phosphorylation of ALDOB and phosphorylation-dependent regulation of GAPDH, together with cross-pathway signaling rewiring, provide novel mechanistic insights into HCC pathogenesis.

Among these, the motif CGTTTCCGGT was identified as an arginine deficiency-responsive DNA element in cancer cells, and C11orf54 showed pronounced downregulation accompanied by reduced chromatin accessibility at its genomic locus. These findings suggest that ADT restricts cancer cell proliferation and migration through chromatin remodeling mediated by the motif CGTTTCCGGT and the downregulation of C11orf54, identifying C11orf54 as a potential target for enhancing the efficacy of arginine deprivation therapy in cancer cells.

Notably, the cotreatment response of H358 cells mirrors clinical trials with KRAS G12C colorectal cancer and NSCLC patients, where the combination of cetuximab with KRAS G12C inhibitors resulted in increased response and progression-free survival. Our findings provide insight into further tailoring EGFR inhibitor cotreatment in KRAS G12C NSCLC patients.

Particularly noteworthy is the downregulation of CYP51A1, which is known to confer TKI resistance under normal circumstances, and therefore directly associated with increased TKI sensitivity in BCR-ABL1 p190-positive cells. Another interesting feature is SPART, whose abundance was increased despite strong promoter hypermethylation, indicating that some transcriptional changes in BCR-ABL1 p190-carrying cells occur independently of promoter methylation and reflect broader regulatory effects of the fusion.

Mechanistic investigation revealed that 10f induces tumor cell apoptosis by modulating the AMPK/mTOR signaling pathway through ASS1 activation. In vivo studies confirmed that 10f possesses significantly improved antitriple-negative breast cancer efficacy compared to SPA, highlighting its substantial therapeutic potential.

Our study uncovers layer-specific molecular landscapes in tongue OLP and identifies KRT17 as a candidate implicated in immune-epithelial crosstalk, providing novel insights into pathogenesis and a potential direction for future therapeutic exploration.

Biological evaluation revealed a strong correlation between the antitumor effects of these compounds and their ability to activate ASS1. For optimal activity, the introduction of a suitable aminoalkyl side chain at the nitrogen atom of dimethyl-Spinosyn A proved to be essential.

Together, these findings reveal a TME-driven, targetable stromal-immune circuit that enables tumors to withstand arginine deficiency-induced metabolic stress. Broadly, our work highlights that mapping and strategically inducing metabolic dependencies can reveal actionable compensatory pathways, offering opportunities to improve cancer therapy.

A cancer-related fatigue model was established by orthotopic injection of 4T1 cells to induce breast cancer, combined with intraperitoneal injection of paclitaxel...The underlying mechanism may involve modulation of Arg biosynthesis and metabolic pathways to maintain systemic arginine homeostasis. These findings provide a preliminary foundation for elucidating the mechanism of Fufang E'jiao Jiang in managing breast cancer chemotherapy-related muscle fatigue.