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Our previous study has identified a depside-type Aspergillusidone G (Asp G) derived from Aspergillus unguis DLEP2008001, which shows excellent neuroprotective activity for 1-methyl-4-phenylpyridinium (MPP+)-induced primary cortical neurons and anti-neuroinflammatory property, promising to be a potential therapeutic agent for Parkinson\u2019s disease (PD). To further explore the anti-PD potential and mechanisms of Asp G, we employed network pharmacology, cellular experiments, and various biological techniques for analysis and validation. The analysis of network pharmacology suggested that Asp G\u2019s anti-PD potential might be attributed to its modulation of inflammation. The data from nitric oxide (NO) detection, qRT-PCR, and Western blot confirmed that Asp G dose-dependently inhibited lipopolysaccharide (LPS)-stimulated NO production, with 40 \u03bcM Asp G suppressing 90.54% of the NO burst compared to the LPS group, and suppressed the overproduction of inflammatory-related factors in LPS-induced BV2 cells. Further protein\u2013protein interaction analysis indicated that matrix metalloproteinase 9 (MMP9), a promising target for PD intervention, was the most likely anti-PD target of Asp G, and the results of gelatin zymography, qRT-PCR, and Western blot validated that Asp G could inhibit the active and inactive forms of MMP9 directly and indirectly, respectively. Notably, the inhibition of 67 kDa-MMP9 by Asp G is expected to compensate for the inability of TIMP-1 to inhibit this form. Furthermore, a selective inhibitor of MMP9 (20 \u03bcM SB-3CT) further potentiated the anti-inflammatory effects of Asp G (20 \u03bcM), with inhibition rate on NO increasing from 27.57% to 63.50% compared to LPS group. In summary, our study revealed that Asp G exerts anti-neuroinflammatory effects by inhibiting MMP9, which provides a valuable lead compound for the development of anti-neuroinflammatory drugs and offers insights into the intervention of PD-associated neuroinflammation. Future studies will further investigate the upstream regulatory mechanisms of Asp G-mediated MMP9 inhibition and its effects in in vivo PD models.<\/jats:p>","DOI":"10.3390\/md23050181","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T03:43:37Z","timestamp":1745379817000},"page":"181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aspergillusidone G Exerts Anti-Neuroinflammatory Effects via Inhibiting MMP9 Through Integrated Bioinformatics and Experimental Analysis: Implications for Parkinson\u2019s Disease Intervention"],"prefix":"10.3390","volume":"23","author":[{"given":"Fangfang","family":"Ban","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4480-4073","authenticated-orcid":false,"given":"Longjian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China"},{"name":"Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6551-684X","authenticated-orcid":false,"given":"Zhiyou","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China"},{"name":"Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yayue","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China"},{"name":"Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China"},{"name":"Collaborative Innovation Center of Seafood Deep 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