Spatial autophagy failure as a pharmacodynamic endpoint for autophagy-targeted dermatological interventions

Autophagy-modulating dermatological interventions include topical, intralesional and systemic therapies, defined bioactive molecules and nutraceutical candidates. Their effects are commonly evaluated using tissue-averaged LC3-II, p62/SQSTM1 and canonical pathway markers. Although these measures support assessment of autophagy pathway engagement, they may miss spatially restricted pharmacodynamic non-response and cannot determine whether persistent local dysfunction reflects inadequate exposure or biology-limited non-response. Here we propose spatial autophagy failure (SAF) as a spatial pharmacodynamic endpoint for autophagy-targeted dermatological interventions. SAF denotes contiguous skin domains showing evidence of impaired autophagic processing and lysosomal dysfunction relative to adjacent tissue. We use photoaged skin and melanophagy as the principal test case. In this setting, persistent hyperpigmented hotspots may partly reflect localized defects in melanosome clearance alongside altered melanogenesis and melanosome transfer. Chronic wounds and pathological scars provide additional dermatological settings in which spatially heterogeneous autophagic capacity may influence treatment response. SAF assessment integrates local drug exposure, local target or pathway engagement, autophagy-lysosome readouts and phenotype maps, distinguishing exposure-limited from biology-limited non-response. Treatment effects can be quantified using total SAF burden, largest-zone size (expressed as area in two-dimensional sections or volume in three-dimensional models), zone contiguity and distance to the nearest phenotype-associated region. These SAF-zone metrics may inform lead selection, formulation and route optimization, dose and schedule selection and pharmacodynamic monitoring. Together, these measurements reframe the central questions: Does an intervention merely shift autophagy markers on average? More importantly, does adequate local exposure produce local target or pathway engagement, restore autophagic processing and improve the corresponding local phenotype?