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aztreonam lysine (Cayston / Corus 1020 / AZLI)

✓ Approved

Gilead Sciences, Inc. · 小分子 · 小分子

什么是 aztreonam lysine？

aztreonam lysine 是一种小分子，由Gilead Sciences, Inc.研发。该药已获批，用于治疗相关适应症，给药途径：Inhaled。

药物档案

商品名Cayston, Corus 1020, AZLI
公司Gilead Sciences, Inc.
药物类别小分子
给药途径Inhaled
状态Approved
来源： ClinicalTrials.gov, Gilead Sciences, Inc.

治疗适应症

aztreonam lysine 针对 3 个适应症，涉及 2 个治疗领域。

治疗领域疾病/病症分期
Infections and infestationsRespiratory tract infection✓ Approved
Infections and infestationsPneumonia pseudomonal✓ Approved
Respiratory, thoracic and mediastinal disordersBronchiectasisPhase III

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Targeting USP7 lactylation suppresses NSCLC tumorigenesis by promoting PINK1 ubiquitination and degradation.

Wang Zhangjie Z, Li Chaoyi C, Zhu Ruiqiu R, Duan Minghao M et al.

Lactylation is an emerging post-translational modification that is well established for its involvement in epigenetic regulation. However, its functional significance and regulatory mechanisms in non-small cell lung cancer (NSCLC) remain poorly understood. In this study, integrated proteomic and lactylomic analyses of clinical NSCLC specimens and matched adjacent normal tissues showed that USP7 (ubiquitin specific peptidase 7) was upregulated and USP7 K1084 lactylation was increased in NSCLC. Knockout of USP7 or inhibition of USP7 lactylation impaired cellular mitophagy, resulting in mitochondrial damage and attenuated NSCLC tumorigenicity. We identified CREBBP/CBP (CREB binding lysine acetyltransferase) as the key lactyltransferase responsible for USP7 K1084 lactylation. USP7 lactylation induced its localization to mitochondria and increased its interaction with PINK1 (PTEN induced kinase 1), promoting PINK1 deubiquitination and stabilization. Pharmacological inhibition of CREBBP reduced USP7 lactylation levels and promoted PINK1 ubiquitination and degradation, exerting antitumor effects in vitro and in vivo. Analysis of NSCLC clinical specimens showed that the protein levels of USP7, CREBBP, and PINK1 were positively correlated, and their high expression was associated with poor patient prognosis. Collectively, our findings establish the CREBBP-USP7-PINK1 axis as a promising therapeutic target for NSCLC treatment.Abbreviations: CHX: cycloheximide; CREBBP/CBP: CREB binding lysine acetyltransferase; DUB: deubiquitinating enzyme; IHC: immunohistochemistry; IP: immunoprecipitation; KO: knockout; LDHA: lactate dehydrogenase A; MS: mass spectrometry; NALA: L-sodium lactate; NSCLC: non-small cell lung cancer; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; ROS: reactive oxygen species; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TUBE: tandem ubiquitin binding entity; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; WT: wild type.

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PubMedCell death and differentiation2026-09-10

KRAS/ERK2-driven stabilization of AARS1 reprograms tumor metabolism and confers Sorafenib resistance in lung adenocarcinoma.

Hu Wenxuan W, Chen Zhike Z, Yang Jian J, Luo Gaomeng G et al.

KRAS is the most frequently mutated oncogene in human cancers, and its G12C variant is highly prevalent in lung adenocarcinoma (LUAD) and predicts poor clinical outcomes. However, the metabolic mechanisms underlying KRAS-driven malignancy and therapeutic resistance remain incompletely understood. Here, we identify alanyl-tRNA synthetase 1 (AARS1) as a previously unrecognized metabolic effector of KRAS signaling. AARS1 protein-but not its mRNA-is markedly upregulated in LUAD tissues, owing to impaired selective autophagic degradation mediated by the E3 ligase TRIM21. Mechanistically, KRAS G12C activates ERK2-dependent phosphorylation of AARS1 at Ser882, disrupting its interaction with TRIM21 and preventing autophagic turnover. Stabilized AARS1 drives metabolic reprogramming by catalyzing lysine lactylation of PDHA1 (K336) and ENO1 (K71), thereby suppressing OXPHOS, enhancing glycolysis, and promoting tumor progression. Importantly, KRAS G12C-induced AARS1 phosphorylation confers resistance to Sorafenib. Blocking AARS1 phosphorylation using the natural compound Hypericin restores autophagic degradation of AARS1, reverses metabolic reprogramming, and markedly sensitizes KRAS-mutant LUAD organoids and PDX models to Sorafenib. These findings uncover AARS1 as a lactate-sensing oncogenic effector downstream of KRAS G12C and highlight the therapeutic potential of targeting AARS1 phosphorylation to overcome drug resistance in LUAD.

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PubMedGeneral physiology and biophysics2026-09-10

USP7/SETDB1 promotes non-small cell lung cancer progression by regulating ferroptosis via NRF2/SLC7A11/GPX4 axis.

Zhang Hongpei H, Fang Yanfeng Y, Wang Xinxin X, Wu Wenting W et al.

Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality. Given the reported associations of both SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) with various cancers and ubiquitin-specific protease 7 (USP7) with NSCLC progression, this study aims to elucidate the role of SETDB1 and USP7 in NSCLC progression. mRNA and protein levels were measured by qRT-PCR and Western blot, respectively. Cell biological phenotypes were evaluated using MTT, EdU, flow cytometry, transwell, and sphere formation assays. Ferroptosis was analyzed by measuring Fe2+, MDA GSH, and ROS levels. Relationship between USP7 and SETDB1 was examined through Co-IP, cycloheximide (CHX) chase, and deubiquitination assays. Xenograft tumor models were established to investigate the role of SETDB1 and USP7 in NSCLC in vivo. In NSCLC tissues and cells, SETDB1 levels were elevated. Knockdown of SETDB1 inhibited NSCLC cell viability, proliferation, invasion, and sphere formation ability, while promoting apoptosis and ferroptosis. Mechanistically, USP7 enhanced the stability of SETDB1 protein by its deubiquitination. USP7 knockdown suppressed NSCLC cell biological behavior by downregulating SETDB1. Moreover, USP7 knockdown repressed in vivo tumor growth of NSCLC. Taken together, USP7 suppresses ferroptosis and enhances growth in NSCLC cells by stabilizing SETDB1 protein through deubiquitination.

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Subcellular sirtuin signaling networks: pivotal regulators of cardiovascular homeostasis and remodeling.

Gao Min M, Li Lanlan L, Li Lin L, Wu Hanyu H et al.

Sirtuins represent a family of highly conserved enzymes, initially identified as Silent Information Regulator 2 (Sir2) in yeast, where they serve as fundamental determinants of longevity. Overexpression of Sir2 in yeast significantly extends lifespan, while its deletion leads to shortened longevity. In mammals, sirtuins (SIRT1-7) represent a conserved family of NAD+-dependent deacylases with diverse catalytic activities. While most members primarily function as deacetylases, SIRT4 exhibits mono-ADP-ribosylation activity, and SIRT5 uniquely targets negatively charged acyl groups, including lysine succinylation, malonylation, and glutarylation. These enzymes act as critical intracellular sensors and regulators widely distributed across diverse tissues. By targeting a broad array of protein substrates, they regulate core biological processes-including genomic stability, metabolism, inflammation, and stress responses. As cardiovascular diseases (CVDs) remain the primary cause of global mortality, driven by complex pathologies such as chronic inflammation and metabolic dysregulation, the sirtuin network has emerged as an indispensable regulator of cardiovascular health. This review systematically elucidates the pivotal roles of sirtuins in cardiovascular homeostasis. We provide an in-depth, subcellular perspective on how nuclear, cytoplasmic, and mitochondrial sirtuins synergistically protect against cardiovascular remodeling, atherosclerosis (AS), and heart failure (HF). Particular emphasis is placed on the molecular mechanisms modulating macrophage polarization and the mitigation of vascular inflammation via the NF-κB signaling pathway. Furthermore, we assess the therapeutic promise of caloric restriction (CR) and pharmacological activators, incorporating recent human clinical evidence. We propose a framework matching sirtuin-based interventions to disease tempo, advocating isoform and compartment-specific strategies for acute and chronic CVDs.

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PubMedFrontiers in genetics2026-09-10

Multi-omics identifies a VIM-associated microglial program linked to lactylation, ferroptosis, and neuroinflammation after spinal cord injury.

Chen Jiayu J, Chen Kai K, Huang Zucheng Z, Tong Jie J

The secondary injury cascade following spinal cord injury (SCI) involves substantial metabolic reprogramming and immune responses. However, whether transcriptional signatures related to lactylation, ferroptosis, and neuroinflammation show coordinated changes after SCI, and which cellular states are associated with these signatures, remain unclear. Public bulk transcriptomic datasets (GSE47681 and GSE5296) and a single-cell RNA-seq dataset (GSE162610) were integrated. Bioinformatic analyses included single-sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network analysis (WGCNA), protein-protein interaction analysis, pseudotime trajectory inference, and in silico perturbation analysis. A C5 unilateral contusion SCI mouse model was used for transcriptomic validation, behavioral assessments, Western blotting, and immunofluorescence. Human peripheral blood RNA-seq data (GSE151371) were used as an exploratory external reference for systemic SCI-associated expression patterns. Bulk transcriptomic analysis revealed coordinated elevation of lactylation-related, ferroptosis-related, and inflammation-related signature scores after SCI, with the highest scores observed at 3 days post-injury. Single-cell RNA-seq localized these signatures predominantly to expanded disease-associated microglia (DAM)-like states. Network screening prioritized vimentin (Vim) as a candidate hub gene associated with the three signatures, and Vim-high pathological microglia exhibited an activated inflammatory-metabolic transcriptional state. In the SCI mouse model, VIM, pan-lysine lactylation (pan-Kla), acyl-CoA synthetase long-chain family member 4 (ACSL4), and interleukin-1β (IL-1β) were upregulated in whole-lesion spinal cord tissue. Immunofluorescence further showed increased VIM, pan-Kla, and ACSL4 signals with spatial overlap within IBA1-positive cells after SCI. Pathological DAM-like microglia represent major microglial states exhibiting concurrent lactylation-related, ferroptosis-related, and inflammatory signatures after SCI. VIM was prioritized as a candidate hub associated with this pathological microglial program. These findings provide a cellular and molecular framework for future mechanistic studies of secondary SCI.

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Impact of PBP3 insertions and β-lactamase-encoding genes on the susceptibility of Escherichia coli isolates belonging to high-risk clones against aztreonam-avibactam and comparator agents.

Castanheira Mariana M, Kimbrough John H JH, Karr Maura M, Sader Helio S HS

We evaluated the presence and phenotypic impact of PBP3 insertions YRIN (n = 44) and YRIK (n = 18) among 124 Escherichia coli isolates belonging to high-risk lineages selected from 1,471 isolates displaying resistance to β-lactams. PBP3 insertions were detected among 62 isolates. YRIN insertions were detected among isolates belonging to ST167 (n = 23), ST361 (n = 7), ST410 (n = 10), ST617 (n = 1), and ST648 (n = 3), while YRIK insertions were observed in ST405 (n = 9), ST410 (n = 5), and ST617 (n = 4). Aztreonam-avibactam inhibited 90.3% of all isolates from high-risk clones and 80.6% of the isolates harboring PBP3 insertions when applying the EUCAST breakpoints. Aztreonam-avibactam inhibited 66.7% of the YRIK-harboring isolates (MIC50/90, 2/16 mg/L) and 86.4% of the ones harboring YRIN insertions (MIC50/90, 1/8 mg/L); however, the susceptibilities to other β-lactams were lower among YRIN isolates (25.6%-60.5%) compared to YRIK (55.6%-88.9%). Overall, ST617 was more resistant to all agents when compared to other STs, regardless of PBP3 insertions or the presence of other examined resistance mechanisms. Acquired β-lactamase genes and OmpC deleterious alterations were present in all isolates. CMY-42, CMY-141, and CMY-145 that have been associated with elevated aztreonam-avibactam MICs were detected among 13 isolates, and 4 (30.8%) were susceptible to this combination. All isolates harboring blaNDM-5 (n = 37) possessed PBP3 insertions. Aztreonam-avibactam inhibited 83.8% of these isolates. Resistance to aztreonam-avibactam is multifactorial, and singular resistance mechanisms are unable to elevate MIC values to resistant categories. Additionally, lineage-specific contributions to resistance play an important role in the overall development of β-lactam resistance, although these mechanisms appear to function outside the known repertoire of resistance-conferring mutations and warrant further study.

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