Liu Kan,Tao Tao,Li Ranhong,Wang Huanping,Wang Li,Wu Haiying
Arsenic exposure is well-established to cause neurotoxicity, but its underlying molecular mechanisms remain unclear. This study investigates the effects of early-life arsenic exposure on the nervous system of offspring. Female mice were exposed to NaAsO₂, and alterations in learning, memory, and hippocampal lesions in offspring were assessed. Transcriptome analysis, protein interaction studies, and cellular experiments were integrated to identify key regulatory factors in arsenic-induced neurotoxicity. Arsenic interacts with HUWE1, significantly downregulating its protein expression. HUWE1 inhibition enhances GPX8 stability by reducing its ubiquitination. GPX8 disrupts histone epigenetic modifications by promoting GSH synthesis and arsenic methylation, leading to elevated H3K9 levels. HUWE1 also interacts with KDM3A, and its inhibition reduces KDM3A-mediated H3K9me1/me2 demethylation, amplifying H3K9me2-mediated transcriptional repression of LARS2 and triggering PANoptosis. This study provides novel molecular insights into arsenic-induced neurotoxicity and highlights potential therapeutic targets to mitigate arsenic-related nervous system damage.
Dysregulation of cytoskeletal proteins has been found in response to DNA damage stress, yet the functional role of cytoskeletal proteins in DNA repair remained unexplored. Here, we found that DNA-damaging agents induced substantial upregulation of smooth muscle-specific cytoskeletal protein smoothelin (SMTN) in colorectal cancer (CRC) cells. Silencing SMTN abrogated G2/M arrest, exacerbated DNA damage, and markedly enhanced the chemosensitivity of CRC cells to various DNA-damaging agents. Notably, SMTN could rapidly accumulate at DNA damage sites within 1 min after laser irradiation, which was indispensable for the initiation of homologous recombination (HR) repair. Mechanistically, SMTN stabilized RAD51 by disrupting its interaction with its E3 ubiquitin ligase HUWE1, thereby maintaining the process of HR repair. To explore the therapeutic role of SMTN, customized cell membrane infused biomimetic liposomes were constructed to ensure rapid delivery of SMTN siRNA specifically into HCT-116 cells, yielding significantly enhanced anti-cancer effects of irinotecan and fuzuloparib both in vitro and in vivo . To summarize, our findings revealed a novel function of SMTN in DNA damage repair and provided a therapeutic strategy of targeting SMTN to enhance the efficacy of DNA damage agents.
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