Phytocarbon Dots as an Oral Nano-Degrader of ENO1 for Alleviating Hepatic Fibrosis

The lack of clinically effective targeted therapies for hepatic fibrosis presents a persistent challenge. In this study, we introduce an innovative oral nanotherapeutic platform based on phytocarbon dots derived from Dianthus superbus (D‑CDs), which function as a target-specific protein degrader. D‑CDs demonstrated potent anti‑fibrotic efficacy in both toxin‑induced and metabolic murine models of liver fibrosis with excellent biocompatibility. Mechanistically, we identified enolase 1 (ENO1) as the direct target. D‑CDs do not inhibit ENO1 enzymatic activity but act as molecular glues that bind to an allosteric site, inducing a conformational change that licenses ubiquitination at K281 and triggers proteasomal degradation. This leads to sustained suppression of the PI3K/AKT‑Smad3 pathway. This ENO1-dependent efficacy was validated through both genetic and pharmacological approaches, establishing a pioneering paradigm of oral nanomedicine for targeted degradation. Importantly, single‑cell transcriptomic and histopathological analyses demonstrated that ENO1 is upregulated during hepatic stellate cell activation and overexpressed in human fibrotic livers, underscoring its clinical relevance. Collectively, our work presents not only a promising therapeutic candidate but also a versatile plant‑based platform for degrading pathological proteins, with broad implications for the treatment of fibrosis and other protein‑driven diseases.