{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T07:00:07Z","timestamp":1790060407894,"version":"4.0.1"},"reference-count":61,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Andrology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Trimethylamine N\u2010oxide (TMAO), a key metabolite derived from gut microbiota dysbiosis, is known to influence various diabetic vascular complications. However, its specific role and the programmed cell death mechanisms underlying the development of diabetes\u2010mediated erectile dysfunction (DMED) remain to be fully elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the mechanism by which TMAO mediates corpus cavernosum smooth muscle cell (CCSMC) dysfunction and promotes DMED in type 1 diabetic rats, with a focus on the involvement of the PI3K\/Akt\u2010regulated PANoptotic\u2010like process.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A type 1 diabetes\u2010mediated erectile dysfunction (T1DMED) rat model was established. Fecal samples were collected for gut microbiota analysis, and serum TMAO levels were measured. Primary CCSMCs were isolated, and cell purity was confirmed via immunofluorescence and flow cytometry. An in vitro TMAO\u2010induced CCSMC injury model was constructed, followed by transcriptome sequencing to identify differentially expressed genes (DEGs) and enriched KEGG signaling pathways. Western blotting and immunohistochemistry (IHC) were performed to detect markers of a PANoptotic\u2010like process (encompassing pyroptosis, apoptosis, and necroptosis) and pathway proteins in penile tissues. Human single\u2010cell RNA sequencing (scRNA\u2010seq) data from penile cavernous tissues were analyzed to compare the PI3K\/Akt axis and the PANoptotic\u2010like process\u2010related genes in CCSMCs between DMED patients and healthy controls. TMAO\u2010injured CCSMCs were treated with the ROS scavenger N\u2010acetylcysteine (NAC) and the PI3K\/Akt inhibitor LY294002. Flow cytometry and Western blotting were used to quantify markers of this death program and pathway activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      T1DMED rats exhibited reduced gut microbiota diversity, with\n                      <jats:italic>Dorea<\/jats:italic>\n                      as the dominant genus. Serum TMAO levels were significantly elevated in the ED group compared with the normal and diabetic non\u2010ED groups.\n                      <jats:italic>Parabacteroides<\/jats:italic>\n                      was positively correlated with TMAO levels, whereas\n                      <jats:italic>Oscillospira<\/jats:italic>\n                      showed a negative correlation. Transcriptome sequencing of TMAO\u2010treated CCSMCs revealed significant enrichment of the PI3K\/Akt signaling pathway. IHC and Western blotting confirmed the marked activation of the PANoptotic\u2010like process in penile tissues of T1DMED rats. Analysis of human scRNA\u2010seq data revealed significant upregulation of PI3K\/Akt signaling and genes associated with the PANoptotic\u2010like program (e.g.,\n                      <jats:italic>CASP1<\/jats:italic>\n                      ,\n                      <jats:italic>CASP3<\/jats:italic>\n                      ,\n                      <jats:italic>CASP8<\/jats:italic>\n                      , and\n                      <jats:italic>MLKL<\/jats:italic>\n                      ) in CCSMCs from DMED patients. Flow cytometry demonstrated increased Caspase\u20101 and Caspase\u20103 positivity in TMAO\u2010treated CCSMCs. NAC significantly reduced both readouts, whereas LY294002 significantly reduced Caspase\u20103 positivity but not Caspase\u20101 positivity. Western blotting confirmed that PI3K and PANoptotic\u2010like markers were upregulated in TMAO\u2010treated CCSMCs, while \u03b1\u2010SMA and eNOS were downregulated. NAC treatment attenuated the TMAO\u2010induced oxidative stress cascade, leading to a reduction in these death markers and restoration of \u03b1\u2010SMA\/eNOS expression. Similarly, LY294002 attenuated several TMAO\u2010induced molecular changes associated with the PANoptotic\u2010like process and partially restored the expression of CCSMC\u2010associated functional markers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Gut microbiota dysbiosis in T1DMED rats was associated with elevated serum TMAO, and TMAO triggered a PANoptotic\u2010like process in CCSMCs via PI3K\/Akt activation, thereby contributing to the progression of DMED.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/andr.70385","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:01:43Z","timestamp":1790056903000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trimethylamine N\u2010oxide, a Gut Microbiota Metabolite, Promotes Diabetes\u2010Mediated Erectile Dysfunction via a PANoptotic\u2010Like Process Involving Pyroptosis, Apoptosis, and Necroptosis in CCSMCs"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2421-7805","authenticated-orcid":false,"given":"Zhan\u2010Sen","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Urology the Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4605-3717","authenticated-orcid":false,"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Infertility and Sexual Medicine the Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Department of Urology State Key Laboratory of Oncology in South China Sun Yat\u2010sen University Cancer Center, Collaborative Innovation Centre for Cancer Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi\u2010Jun","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Infertility and Sexual Medicine the Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Gastroenterology Center the First Hospital of Hebei Medical University  Shijiazhuang Hebei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine Guangdong Women and Children Hospital  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia\u2010Xin","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Surgery the Affiliated Foshan Women and Children Hospital, Guangdong Medical University  Foshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo\u2010Wen","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Infertility and Sexual Medicine the Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su\u2010Shun","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Infertility and Sexual Medicine the Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Chen","family":"Luan","sequence":"additional","affiliation":[{"name":"Department of Infertility and Sexual Medicine the Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010He","family":"Quan","sequence":"additional","affiliation":[{"name":"Department of Urology Shenzhen Hospital of Southern Medical University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4420-3152","authenticated-orcid":false,"given":"Jin\u2010Ming","family":"Di","sequence":"additional","affiliation":[{"name":"Department of Urology the Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Infertility and Sexual Medicine the Third Affiliated Hospital of Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2016.23"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","unstructured":"NIH Consensus Conference. 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