The impact of the let-7 family on the pathophysiological mechanisms of traumatic brain injury: a systematic review

Natalia Radenza¹Renata Mangione^2,3Saviana Antonella Barbati³francesco Bellia¹Giuseppe Caruso³Antonio Belli⁴Giuseppe Lazzarino⁵BARBARA TAVAZZI³Giacomo Lazzarino^3*Angela Maria Amorini¹Valentina Di Pietro^6*

• ¹Universita degli Studi di Catania Dipartimento di Scienze biomediche e biotecnologiche, Catania, Italy
• ²Saint Camillus International University of Health and Medical Sciences, Rome, Italy
• ³Faculty of Medicine, UniCamillus-Saint Camillus International University of Health and Medical Sciences, 00131 Rome, Italy;, Rome, Italy
• ⁴University of Birmingham Institute of Inflammation and Ageing, Birmingham, United Kingdom
• ⁵eLTA-Biotech srl, Paternò (CT), Italy
• ⁶Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

Background: The let-7 family of microRNAs (miRNAs) plays a crucial role in regulating key biological functions including cell differentiation, inflammation, metabolism, and proliferation. Their dysregulation has been implicated in a variety of diseases, including cancer and neurological disorders. Despite extensive knowledge of their roles in normal physiology and disease, the involvement of let-7 miRNAs in the pathophysiology of Traumatic Brain Injury (TBI) remains incompletely understood. Objective: To systematically identify and analyze the differential expression of let-7 family members following TBI across human and animal models, and to assess their potential role as diagnostic biomarkers and therapeutic targets. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Literature was retrieved from PubMed, EMBASE, and Web of Science using predefined keywords based on a PICOs framework. Studies were included if they reported on let-7 family expression post-TBI in humans or animals. Risk of bias was assessed using the Evidence Project and SYRCLE tools. Data were extracted regarding species, sample type, TBI model, time points, and let-7 expression profiles. PROSPERO 2025 CRD420251129282. Available from https://www.crd.york.ac.uk/PROSPERO/view/CRD420251129282. Results: Out of 41 initially identified records, 15 studies met the inclusion criteria. In human studies, upregulation of let-7 family members (e.g., let-7a, b, c, f, i) was consistently observed in peripheral biofluids (serum, plasma, saliva) following mild to severe TBI. However, cerebrospinal fluid (CSF) levels showed mixed or decreased expression patterns. In contrast, animal studies showed predominant downregulation of let-7 in brain tissues post-TBI, with some evidence suggesting their role in modulating neuroinflammatory responses, apoptosis, and energy metabolism. Let-7c and let-7i were particularly implicated in the modulation of microglial activation, IL-6 regulation, and STING signaling pathways. Limited mechanistic data suggest let-7's involvement in glucose metabolism, N-acetylaspartate homeostasis, and antioxidant response. Conclusions: The let-7 family exhibits divergent expression trends in tissue and biofluids following TBI, highlighting their potential as non-invasive biomarkers. Their regulatory roles in inflammation, metabolism, and neuroprotection suggest therapeutic promise. However, current evidence remains fragmented, and further mechanistic studies are necessary to validate their function in post-TBI recovery and to explore their utility as clinical biomarkers or treatment targets.