NeuroHIV affects approximately 30–60% of people living with HIV-1 (PLWH) and is characterized by varying degrees of cognitive impairments, presenting a multifaceted challenge, the underlying cause of which is chronic, low-level neuroinflammation. Such smoldering neuroinflammation is likely an outcome of lifelong reliance on antiretrovirals coupled with residual virus replication in the brains of PLWH. Despite advancements in antiretroviral therapeutics, our understanding of the molecular mechanism(s) driving inflammatory processes in the brain remains limited. Recent times have seen the emergence of non-coding RNAs (ncRNAs) as critical regulators of gene expression, underlying the neuroinflammatory processes in HIV infection, NeuroHIV, and their associated comorbidities. This review explores the role of various classes of ncRNAs and their regulatory functions implicated in HIV infection, neuropathogenesis, and related conditions. The dysregulated expression of ncRNAs is known to exacerbate the neuroinflammatory responses, thus contributing to neurocognitive impairments in PLWH. This review also discusses the diagnostic and therapeutic potential of ncRNAs in HIV infection and its comorbidities, suggesting their utility as non-invasive biomarkers and targets for modulating neuroinflammatory pathways. Understanding these regulatory roles could pave the way for novel diagnostic strategies and therapeutic interventions in the context of HIV and its comorbidities.

Cocaine misuse induces microglial activation and neuroinflammation, contributing to neurodegeneration and behavioral impairments. Prior studies have shown that cocaine induces mitochondrial dysfunction, dysregulated mitophagy, and lysosomal impairment in microglia. Here, we investigated the therapeutic potential of N-acetylcysteine (NAC) in mitigating cocaine-induced microglial activation and neuroinflammation. Mouse primary microglial cells (MPMs) were pretreated with NAC (5 mM) for 1 h prior to cocaine exposure (10 µM, 24 h) and analyzed for markers of microglial activation, mitophagy, and lysosomal integrity using Western blot, Seahorse assays, lysosomal pH, and membrane potential measurements. In vivo, C57BL/6N mice received NAC (200 mg/kg, i.p.) 1 h before daily cocaine injections (20 mg/kg, i.p.) for 7 days. Behavioral assays (open field, novel object recognition) and brain biomarker analyses (frontal cortex, hippocampus) were performed. Cocaine exposure elevated CD11b, mitophagy markers (PINK1, PARK, and DLP1), and autophagy proteins (Beclin1, and p62), while impairing mitochondrial and lysosomal functions. NAC pretreatment restored mitochondrial and lysosomal function, reduced reactive oxygen species, and normalized protein expression. In vivo, NAC also alleviated cocaine-induced microglial activation and behavioral deficits. These findings highlight NAC as a promising therapeutic agent to counteract cocaine-mediated neuroinflammation and neurotoxicity.