Exploring Castanea sativa Shells (CSSs) as a Source of AKR1B1 and AKR1B10 Inhibitors: From Extraction to Bioactivity Testing

Chestnut shells are widely recognized as a source of bioactive compounds, including polyphenols and other antioxidant molecules. The industrial chestnut food chain generates large amounts of this by-product, which represents both a waste disposal challenge and a potential source of promising biomolecules. Thermal treatments occurring during industrial processing, however, may affect both chemical composition and bioactivity. Characterization of the chemical composition and biological activity of chestnut shells can contribute to the valorisation of this industrial by-product. Understanding which molecular alterations are caused by the processing is essential to assess the real potential of chestnut shell biomass. This study provides a comparative analysis of <i>Castanea sativa</i> shells, both raw and industrially processed. Evaluation was performed at different levels, exploiting mass spectrometry-based metabolite profiling, Total Phenolic Index analysis, antioxidant capacity, and inhibitory activity against AKR1B and AKR1B10, two reductases involved in key physiopathologic pathways. A comparison between extraction solvents (water and ethanol) and processing status (raw versus industrially processed) was performed. Overall, our results support the view that chestnut shell residues represent a valuable source of bioactive extracts. In a circular economy framework, such extracts could be developed to act on AKR1B1/AKR1B10 activity and oxidative stress, thereby contributing to the valorisation of chestnut processing by-products.