Co-administration of UDP-003 (7KC extractor) and lupeol (TFEB/autophagy activator) achieves synergistic atherosclerot...

IF UDP-003 (Cyclarity Therapeutics; engineered hydroxypropyl-β-cyclodextrin, 7KC-selective; subcutaneous administration at the monotherapy-equivalent dose range suggested by existing pharmacokinetic data, estimated 200–400 mg/kg, 3×/week) is co-administered with lupeol (a pentacyclic triterpenoid TFEB/autophagy activator, 50 mg/kg/day oral gavage) to male and female ApoE-/- mice, aged 20 weeks with 12 weeks of established high-fat diet (HFD)-induced atherosclerosis (a post-plaque-establishment regression model),

THEN the following outcomes, measured at 8 weeks post-treatment initiation, will exceed those of UDP-003 monotherapy: (a) aortic arch 7KC content reduced by ≥50% from vehicle control (vs. ~25–35% estimated for UDP-003 monotherapy), quantified by isotope-dilution LC-MS/MS with d7-7KC internal standard; (b) plaque efferocytosis index (TUNEL+/Mac3+ co-positive ratio) improved by ≥40% relative to vehicle; (c) necrotic core fraction of en face Oil Red O plaque area reduced by ≥30%; and (d) aortic sinus CD68+ macrophage density reduced by ≥25%,

BECAUSE the following mechanistic chain operates in series:

1. Chronic 7KC accumulation within foam-cell lysosomes is the primary driver of lysosomal dysfunction in atherosclerotic plaques. Lysosomal function is markedly impaired in atherosclerosis, and restoring lysosomal competence in macrophages confers measurable anti-atherogenic effects in preclinical models (Lysosomal biogenesis induction is anti-atherogenic)[https://doi.org/10.1161/ATVBAHA]. UDP-003 monotherapy removes the lysosomal 7KC burden — reducing lipid droplet accumulation by 20–31% and promoting urinary 7KC excretion in vivo — but does not rebuild the depleted lysosomal compartment left behind after years of 7KC-mediated damage (UDP-003 extracts 7KC from foam cells and restores phagocytosis 15–20%)[https://pmc.ncbi.nlm.nih.gov/articles/PMC10634755/].

2. After 7KC is extracted by UDP-003, the residual lysosomal compartment remains quantitatively diminished and functionally under-powered. [SPECULATIVE] Chronic 7KC exposure suppresses TFEB nuclear translocation via mTORC1 hyperactivation on lysosomal membranes. Even once the 7KC ligand is removed by UDP-003, the TFEB repression state persists as an epigenetic memory of lysosomal stress, limiting the biogenesis rebound. This is consistent with the observation that lysosomal dysfunction in atherosclerosis is a stable, self-reinforcing state that requires active induction of a biogenesis program to rescue (Inducing lysosomal biogenesis confers anti-atherogenic effects)[https://doi.org/10.1161/ATVBAHA].

3. Lupeol acts as an autophagy-competence restorer in exactly this cellular context. Lupeol promotes an anti-inflammatory, autophagy-competent macrophage phenotype that resists the key proatherogenic effects of 7KC, operating through pathways that include autophagy flux restoration and suppression of the NF-κB/NLRP3 inflammatory axis (Lupeol promotes autop...

SENS category: LysoSENS

Key references: • doi.org/10.1161/ATVBAHA]. • doi.org/10.1155/2020/1232816]. • doi.org/10.1111/bph.15209]. • doi.org/10.1073/pnas.1301929110]. • doi.org/10.1161/ATVBAHA],