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Repeat-associated non-AUG (RAN) translation of the expanded repeat generated dipeptide repeat proteins (DPRs), which disrupted multiple cellular processes and contributed to neurodegeneration. Emerging evidence indicated that disease pathogenesis involved both gain-of-function (GOF) and loss-of-function (LOF) mechanisms. DPR-mediated GOF toxicity induced ribosomal dysfunction, nucleolar stress, proteostatic impairment, and neuronal injury, whereas C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis. Neuronal injury further promoted the release of damage-associated signals that triggered secondary microglial activations and chronic neuroinflammations. This review summarized current knowledge of DPR biology, microglial dysfunction, and their contributions to disease progression in C9ORF72-associated ALS\/FTD. Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed. In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown. Together, these findings provided important insights into disease mechanisms and potential avenues for improved clinical management.<\/jats:p>","DOI":"10.3390\/ijms27125537","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T14:37:42Z","timestamp":1781879862000},"page":"5537","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microglial Dysfunction Induced by C9ORF72 Dipeptide Repeat Proteins: Biomarker and Therapeutic Perspectives"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6720-257X","authenticated-orcid":false,"given":"Niti","family":"Sharma","sequence":"first","affiliation":[{"name":"Lab of Ageing-Related Diseases, Bionano Research Institute, Gachon University, 1342 Seongnam-daero, Sujung-gu, Gyeonggi-do, Seongnam-si 461-701, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8123-6183","authenticated-orcid":false,"given":"Seong Soo A.","family":"An","sequence":"additional","affiliation":[{"name":"Lab of Ageing-Related Diseases, Bionano Research Institute, Gachon University, 1342 Seongnam-daero, Sujung-gu, Gyeonggi-do, Seongnam-si 461-701, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","first-page":"2909168","article-title":"Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion","volume":"2019","author":"Kirincich","year":"2019","journal-title":"Behav. 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