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Although lithium serves as the first-line treatment for BD, its underlying therapeutic mechanism and potential effects on T2D remain incompletely understood. This study identified the PI3K\/AKT pathway as a key link between these disorders. Using an ordinary differential equation (ODE) model that integrates the PI3K\/AKT pathway with the phosphatidylinositol (PI) cycle, we simulated lithium\u2019s regulatory effects in BD treatment. Our simulations revealed that lithium\u2019s primary inhibitory effect on GSK3\u03b2 stems from direct binding, which restores insulin sensitivity, suggesting potential benefits for both BD and T2D, particularly in their comorbid state. Additionally, molecular docking studies indicated that curcumin, a potentially safer alternative to lithium, exhibits enhanced anti-inflammatory properties by binding to both GSK3\u03b2 and p38 MAPK. These findings provide novel insights into the molecular mechanisms connecting BD and T2D and propose new therapeutic strategies for their management.<\/jats:p>","DOI":"10.3390\/ijms262010026","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T10:12:29Z","timestamp":1760523149000},"page":"10026","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Computational Modeling of PI3K\/AKT Pathway in Bipolar Disorder and Type 2 Diabetes: Implications for Lithium Treatment and Curcumin as a Potential Alternative"],"prefix":"10.3390","volume":"26","author":[{"given":"Jing","family":"Li","sequence":"first","affiliation":[{"name":"Wisdom Lake Academy of Pharmacy, Xi\u2019an Jiaotong-Liverpool University, Suzhou 215123, China"},{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Wisdom Lake Academy of Pharmacy, Xi\u2019an Jiaotong-Liverpool University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1057-3000","authenticated-orcid":false,"given":"Yajunzi","family":"Wang","sequence":"additional","affiliation":[{"name":"Wisdom Lake Academy of Pharmacy, Xi\u2019an Jiaotong-Liverpool University, Suzhou 215123, China"},{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Hao","sequence":"additional","affiliation":[{"name":"Wisdom Lake Academy of Pharmacy, Xi\u2019an Jiaotong-Liverpool University, Suzhou 215123, China"},{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0802-6446","authenticated-orcid":false,"given":"Lei","family":"Fu","sequence":"additional","affiliation":[{"name":"Wisdom Lake Academy of Pharmacy, Xi\u2019an Jiaotong-Liverpool University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6542-3181","authenticated-orcid":false,"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Wisdom Lake Academy of Pharmacy, Xi\u2019an Jiaotong-Liverpool University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1111\/j.1524-4733.2010.00768.x","article-title":"Functional Impairment and Disability across Mood States in Bipolar Disorder","volume":"13","author":"Rosa","year":"2010","journal-title":"Value Health J. 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