<p>Huntington’s disease (HD) is a fatal neurodegenerative disorder marked by progressive neuronal loss with prominent degeneration of the striatum. Although classically viewed as a cell-autonomous disorder, emerging evidence suggest non-cell-autonomous spread of the pathology but without clear mechanistic details. In this study, we demonstrate that the secretome of a truncated mHTT expressing HD150Q cells contains soluble, aggregated, and exosome-associated mHTT species that are efficiently internalized by wild-type striatal neuronal cells. This led to hallmark HD-like dysfunctions including suppressed mitochondrial biogenesis regulators (<i>Bdnf</i>, <i>Nrf1</i>), depleted ATP, and elevated mitochondrial and cytosolic ROS, consistent with bioenergetic collapse and redox stress. Further, secretome exposure activated the unfolded protein response, repressed DRD1α/DRD2–BDNF transcriptional circuitry and reduced neuronal viability. Fractionation experiments demonstrated that both aggregated and vesicle associated mHTT species were pathogenic, exerting independent yet additive bioenergetic toxicity. Strikingly, peripheral immune cells exposed to the same secretome exhibited a robust pro-inflammatory response, mirroring systemic immune activation seen in HD patients. These findings establish mHTT-containing secretome as a transmissible pathogenic entity capable of reprogramming both neuronal and immune cells. Importantly, we show that treatment of donor HD cells with decanoic acid (C10:0)—a medium-chain fatty acid, abolishes the secretome’s pathogenic effect on both neuronal and immune cells. Together, our results establish extracellular mHTT as a mechanistically sufficient and pharmacologically targetable driver of disease spread. Importantly, this work provides proof-of-concept that pharmacological modulation of the secretome using decanoic acid represents a promising strategy for limiting propagation and progression of Huntington’s disease.</p>