bims-meprid 2025-02-23 papers

Redox Biol. 2025 Feb 15. pii: S2213-2317(25)00066-7. [Epub ahead of print]81 103553

Histone lactylation drives liver cancer metastasis by facilitating NSF1-mediated ferroptosis resistance after microwave ablation.

Jiayan Huang, Huijing Xie, Ju Li, Xiaotong Huang, Yunshi Cai, Rui Yang, Dongmei Yang, Wuyongga Bao, Yongjie Zhou, Tao Li, Qiang Lu.

Insufficient microwave ablation (IMWA) is linked to aggressive hepatocellular carcinoma (HCC) progression. An increase in lactate levels after sublethal heat stress (HS) has been confirmed in HCC. However, the role of lactate-related histone lactylation in the progression of HCC caused by sublethal HS remains unclear. Here, we found that the metastatic potential of HCC increased in a lactate-dependent manner after IMWA. Moreover, sublethal HS triggered an increase in H3K18la modification, as validated in a cell-derived xenograft mouse model and human HCC samples. By performing an integrated analysis of proteomic and transcriptomic profiles, we revealed that HCC cells exhibited increased intracellular iron ion homeostasis and developed resistance to platinum-based drugs after exposure to sublethal HS. We subsequently integrated proteomic and transcriptomic data with H3K18la-specific chromatin immunoprecipitation (ChIP) sequencing to identify candidate genes involved in sublethal heat treatment-induced HCC cell metastasis. Mechanically, an increase in H3K18la modification enhanced the transcriptional activity of NFS1 cysteine desulfurase (NFS1), a key player in iron‒sulfur cluster biosynthesis, thereby reducing the susceptibility of HCC to ferroptosis after IMWA. Knocking down NFS1 diminished the metastatic potential of sublethally heat-treated HCC cells. Additionally, NFS1 deficiency exhibited a synergistic effect with oxaliplatin, leading to the significant inhibition of the metastatic capability of HCC cells both in vitro and in vivo, regardless of sublethal HS treatment. In conclusion, our study revealed the oncogenic role of histone lactylation in HCC after IMVA. We also bridged histone lactylation with ferroptosis, providing novel therapeutic targets for HCC following microwave ablation, particularly when combined with oxaliplatin-based chemotherapy.

Keywords: H3K18la; Hepatocellular carcinoma; NFS1; Oxaliplatin; Thermal ablation

DOI: https://doi.org/10.1016/j.redox.2025.103553

Int Immunopharmacol. 2025 Feb 15. pii: S1567-5769(25)00239-5. [Epub ahead of print]150 114249

ACLY inhibitor reduced Porphyromonas gingivalis-induced pyroptosis by suppressing microtubules acetylation in macrophages.

Huimin Mao, Feng Guo, Chenxu Wang, Ke Jiang, Houxuan Li, Lang Lei.

OBJECTIVES: This study aimed to investigate the effect of acetylation of α-tubulin induced by ATP-citrate lyase (ACLY) activation on pyroptosis process in mouse bone marrow derived macrophages (BMDMs).
MATERIALS AND METHODS: Level of phospho-ACLY was assessed in normal and inflamed gingiva. Mouse BMDMs were harvested and infected with Porphyromonas gingivalis. The mRNA and protein levels of genes were analyzed by real-time quantitative PCR and western blotting, respectively. Polymerization and acetylation of microtubules were detected with immunofluorescence. Lactate dehydrogenase (LDH) activity assay, immunofluorescence, and ELISA were performed to determine pyroptosis in P.gingivalis-induced BMDMs.
RESULTS: Elevated expression of phospho-ACLY was observed in the inflamed gingiva. P. gingivalis infection was shown to promote pyroptosis in mouse BMDMs. Moreover, P. gingivalis-induced BMDMs showed increased phospho-ACLY, as well as polymerization and acetylation of microtubules. Inhibition and knockdown of ACLY showed depolymerization and decreased acetylation of microtubules, thus resulting in reduced P. gingivalis-induced pyroptosis in BMDMs.
CONCLUSIONS: Our findings suggest that ACLY-mediated dynamics of microtubules participate in the progress of periodontitis. P. gingvalis-triggered phospho-ACLY target the microtubule cytoskeleton by influencing acetylation of tubulin, facilitating NLRP3 inflammasome activation and pyroptosis.

Keywords: ACLY; Acetylation; Macrophages; Microtubules; Periodontitis; Pyroptosis

DOI: https://doi.org/10.1016/j.intimp.2025.114249

Nat Microbiol. 2025 Feb 19.

Intestinal crypt microbiota modulates intestinal stem cell turnover and tumorigenesis via indole acetic acid.

Shuning Zhang, Lihua Peng, Shyamal Goswami, Yuchen Li, Haiyue Dang, Shuli Xing, Panpan Feng, Giulia Nigro, Yingying Liu, Yingfei Ma, Tianhao Liu, Jiahua Yang, Tinglei Jiang, Yingnan Yang, Nick Barker, Philippe Sansonetti, Parag Kundu.

Intestinal crypts harbour a specific microbiota but whether and how these bacteria regulate intestinal stem cells (ISCs) or influence colorectal cancer (CRC) development is unclear. Here we screened crypt-resident bacteria in organoids and found that indole acetic acid (IAA) secreted by Acinetobacter radioresistens inhibits ISC turnover. A. radioresistens inhibited cellular proliferation in tumour slices from CRC patients and inhibited intestinal tumorigenesis and spheroid initiation in APCMin/+ mice. Targeted clearance of A. radioresistens from colonic crypts using bacteriophage increased EphB2 expression and consequently promoted cellular proliferation, ISC turnover and tumorigenesis in mouse models of CRC. The protective effects of A. radioresistens were abrogated upon deletion of trpC to prevent IAA production, or upon intestine-specific aryl hydrocarbon receptor (AhR) knockout, identifying an IAA-AhR-Wnt-β-catenin signalling axis that promotes ISC homeostasis. Our findings reveal a protective role for an intestinal crypt-resident microbiota member in tumorigenesis.

DOI: https://doi.org/10.1038/s41564-025-01937-5