Aug 2026· British Journal of Cancer· 0 citations· 42 references
Medicine
TL;DR
Targeting CTPS1 with STP938, alone or in combination with osimertinib, represents a promising therapeutic strategy and supports CTPS1 as a targetable vulnerability in lung adenocarcinoma.
Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer; however, its prognosis remains poor, and the underlying molecular mechanisms have yet to be fully elucidated. In this study, a prognostic model was constructed based on manganese metabolism-related genes, which effectively stratifies patients with LUAD with different prognoses and drug sensitivity. Mendelian randomization analysis identified glutathione peroxidase 3 (GPX3) as a key prognostic gene, which was downregulated in LUAD and significantly correlated with favorable outcomes. Functionally, GPX3 was found to inhibit LUAD cell proliferation, invasion, and metastasis while promoting apoptosis. Mechanistically, GPX3 binds to heat shock protein β-1 (HSPB1), induces its ubiquitination, and facilitates its degradation, thereby activating the Hippo signaling pathway and suppressing malignant phenotypes in LUAD cells. In summary, this study not only established a robust prognostic model based on manganese metabolism-related genes but also uncovered the critical regulatory role of the GPX3/HSPB1/yes-associated protein (YAP) axis in LUAD progression, underscoring the therapeutic potential of targeting GPX3.
Si-Xuan Wu, He Huang, Junfan Pan et al.· Cell Reports· 0 citations
This study identifies TPI1 as a key tumor-promoting factor and independent prognostic biomarker in HNSCC, providing a promising therapeutic target for overcoming ferroptosis evasion in HNSCC.
Rui Ye, Zhihua Xu, Ye-Hai Liu· Frontiers in Genetics· 0 citations
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited therapeutic advancements despite progress in early detection. Serine hydroxymethyltransferase 2 (SHMT2), a key metabolic enzyme, and fructose-1,6-bisphosphate aldolase A (ALDOA), a glycolytic enzyme, are implicated in tumor progression. However, the molecular mechanisms linking SHMT2 and ALDOA in GC remain unclear. This study investigates how SHMT2 regulates ALDOA expression via m6A RNA modification to drive GC malignancy. Bioinformatic analyses (TCGA, LinkedOmics, and SRAMP) were used to assess SHMT2 expression in GC patients and identify its correlated genes. In vitro experiments (CCK-8, EdU, Transwell, and wound healing) evaluated the effects of SHMT2 overexpression or knockdown on GC cell proliferation, migration, invasion, and glycolysis. m6A modification of ALDOA was analyzed via MeRIP-PCR and dual-luciferase assays, while RNA stability was assessed using actinomycin D treatment. Xenograft models validated SHMT2's role in vivo. SHMT2 was upregulated in GC tissues and cell lines, correlating with advanced tumor stages and poor prognosis. SHMT2 knockdown suppressed GC cell viability, migration, invasion, and glycolysis, while overexpression enhanced these traits. Mechanistically, SHMT2 increased S-adenosylmethionine levels, promoting ALDOA m6A modification, likely mediated through the predicted site 1 (position 291). This modification stabilized ALDOA mRNA via IGF2BP1 recognition, an m6A reader. ALDOA overexpression reversed the tumor-suppressive effects of SHMT2 knockdown. In vivo, SHMT2 depletion reduced tumor growth and Ki67 expression in xenograft models. In conclusion, SHMT2 drives GC progression by enhancing ALDOA expression through m6A modification and IGF2BP1-mediated stabilization. Targeting the SHMT2-ALDOA axis represents a promising therapeutic strategy for gastric cancer.
BACKGROUND
Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer and remains a major cause of cancer-related mortality. Despite advances in targeted therapies, tumor heterogeneity and acquired resistance frequently undermine clinical outcomes. This study aimed to identify novel oncogenic drivers and underlying mechanisms in LUAD.
METHODS
We examined cellular retinoic acid-binding protein 2 (CRABP2) expression in human LUAD specimens and evaluated its functional role through in vitro assays (cell proliferation, migration, invasion, and apoptosis) and in vivo xenograft tumor growth. Mechanistic exploration involved RNA sequencing, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and immunoblotting for the nuclear factor kappa B (NF-κB) signaling components, along with rescue experiments to dissect the pathway dependency.
RESULTS
CRABP2 was identified as a candidate oncogene in LUAD. Functional assays confirmed that CRABP2 promoted proliferation, migration, and invasion, suppressed apoptosis, and accelerated xenograft tumor growth. Mechanistically, CRABP2 potentiated retinoic acid (RA) signaling and activated the NF-κB pathway, as evidenced by enhanced inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) phosphorylation, subsequent NF-κB inhibitor alpha (IκBα) phosphorylation, and nuclear translocation of total and phosphorylated p65. Rescue experiments revealed that CRABP2‑induced NF-κB activation is RA-dependent and that this activation mediates the oncogenic effects of CRABP2.
CONCLUSIONS
Our findings establish a CRABP2/RA/NF‑κB axis that drives LUAD progression, highlighting this pathway as a potential therapeutic target for intervention in LUAD.
Xi-Rui Zhu, Biao Fan, Qingyang Lei et al.· Frontiers in Bioscience· 0 citations
BACKGROUND
Lung adenocarcinoma (LUAD) is a malignant tumor characterized by high invasiveness and poor prognosis. Although phospholipid phosphatase 3 (PLPP3) is downregulated in LUAD, its functional mechanisms in this cancer remain poorly understood.
METHODS
The expression levels of PLPP3 and membrane-associated RING-CH-1 (MARCH1) in LUAD tissues and cells were evaluated using the Gene Expression Profile Interactive Analysis (GEPIA) database, Gene Expression Omnibus (GEO), quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot techniques. The roles of MARCH1 and PLPP3 in LUAD were investigated through functional assays (colony formation, flow cytometry, wound healing assay, Transwell assay, nude mouse xenograft model, immunohistochemistry (IHC), Fe²⁺ detection, malondialdehyde (MDA) detection, glutathione (GSH) detection, lipid reactive oxygen species (ROS) detection, and cell counting kit-8 (CCK-8) assay). Mechanistic studies, including co-immunoprecipitation (Co-IP), ubiquitination assay, and cycloheximide (CHX) chase experiments, were conducted to elucidate their potential regulatory mechanisms.
RESULTS
PLPP3 was downregulated in LUAD. PLPP3 suppressed cell proliferation, promoted apoptosis, inhibited migration and invasion in LUAD cells, and impaired tumor growth in vivo. In addition, PLPP3 downregulated glutathione peroxidase 4 (GPX4) and upregulated acyl-coA synthetase long chain family member 4 (ACSL4), elevated Fe²+ and MDA levels, reduced GSH levels, and increased lipid ROS levels. These effects could be reversed by ferroptosis inhibitor Ferrostatin‑1 (Fer‑1) and Liproxstatin-1 (Lip-1). Furthermore, MARCH1 promoted the K48- and K63-linked polyubiquitination of PLPP3, thereby leading to the rapid proteasomal degradation of PLPP3. Rescue experiments demonstrated that MARCH1 enhanced the malignant phenotypes of LUAD cells, inhibited ferroptosis, and promoted tumor progression by suppressing PLPP3 expression.
CONCLUSION
MARCH1 promotes the malignant progression of LUAD by regulating the ubiquitination of PLPP3, highlighting its potential as a therapeutic target.
Yi Li, Jingxian Yang, Xia Wang et al.· Pathology, Research and Prac...· 0 citations
Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, is associated with substantial global mortality. Nuclear receptor coactivator 5 (NCOA5) has been implicated in several malignancies; however, its functional role and regulatory mechanisms in LUAD remain largely unknown. In this study, NCOA5 expression was evaluated in 94 paired LUAD and adjacent tissues using immunohistochemistry, RT-PCR, and Western blotting. Functional analyses were conducted using shRNA knockdown, CRISPR-mediated knockout, and overexpression models to assess the effects of NCOA5 on LUAD cell proliferation, migration, invasion, apoptosis, cell cycle progression, and organoid formation. Xenograft models were used to validate tumorigenicity in vivo. IP-MS and co-immunoprecipitation identified NCOA5-interacting proteins, while ChIP-seq and dual-luciferase assays interrogated downstream transcriptional regulation. NCOA5 was significantly upregulated in LUAD tissues and associated with advanced stage, poor differentiation, and reduced overall survival, serving as an independent prognostic factor (
P
< .040). NCOA5 knockdown inhibited LUAD cell proliferation, migration, invasion, induced G0/G1 arrest, promoted apoptosis, reduced organoid formation, and suppressed xenograft growth, whereas NCOA5 overexpression produced the opposite effects. Among 39 candidate interacting proteins identified by IP-MS, ZCCHC3 was validated as a direct NCOA5-binding partner. ZCCHC3 depletion phenocopied NCOA5 loss and reversed NCOA5-induced proliferation, migration, invasion, and colony formation, supporting a functional NCOA5–ZCCHC3 interaction. ChIP-seq analysis identified fibroblast growth factor 22 (FGF22) as a direct transcriptional target of NCOA5. FGF22 was markedly downregulated in LUAD tissues and higher FGF22 expression was associated with improved patient survival. NCOA5 suppressed FGF22 transcription, while NCOA5 inhibition increased FGF22 expression. Functionally, FGF22 knockdown enhanced LUAD aggressiveness, whereas FGF22 restoration abrogated the oncogenic effects of NCOA5 in vitro and in vivo. Collectively, these findings identify a previously unrecognized NCOA5–ZCCHC3/FGF22 axis that drives LUAD progression and provide new mechanistic insight into the role of NCOA5 in LUAD biology.
Yiran Yu, Wen Jin, Erdun Chaogetu et al.· Cell Death & Disease· 0 citations
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