Owing to their nutritional, culinary, and nutraceutical, mushrooms are worldwide consumed and appreciated. Moreover, many of these mushrooms are also known as medicinal mushrooms since they possess several pharmacological properties attributable to a huge number of bioactive compounds derived from their sporophores. Several studies are available in the literature about in vitro and in vivo mechanisms of actions of such bioactive compounds. Most of these surveys are focused on macrofungi belonging to the genera Pleurotus, Ganoderma, or specific taxa such as Agaricus bisporus, Agaricus blazei, Boletus eduliInonotus obliquus, Hericium erinaceus, Lentinula edodes, and Grifola frondose. On the other hand, there is a lack of information on the under investigated ecological group of freshwater fungi. These fungi play a very important role in freshwater environments and some of them, belonging to Basidiomycota, are also edible and largely consumed. In this review we collected information about the medicinal properties of freshwater macro- and micromycetes. Among them, macrofungi, such as Amanita vaginata, Armillaria mellea, Armillaria tabescens, Astraeus hygrometricus, Auricularia auricula-judae, Bjerkandera adusta, Bovista nigrescens, Calocybe gambosa, Candolleomyces candolleanus, Collybia dryophila, Coprinus comatus, Cyclocybe cylindracea, Hypsizygus ulmarius, Inonotus hispidus, Lactarius controversus, Lentinus tigrinus, and Schizophyllum commune, observed in riparian habitat, and microfungi, such as Penicillium aculeatum, P. chrysogenum, and Fusarium incarnatum, isolated from aquatic plants, have been reported to have antimicrobial, anticancer, anti-inflammatory, antioxidant, antidiabetic, immunomoludatory, hypoglycaemic, and other pharmaceutical activities. Such fungal species are noteworthy since they represent an important quote of biodiversity to preserve their fundamental ecological role and a possible solution for different health problems for humans and animal farms.

Pleurotus nebrodensis, a rare endemic Sicilian mushroom with notable gastronomic and medicinal value, attracts interest for its potential antioxidant properties, though data on its biological effects in skin models are lacking. This study evaluated the antioxidant activities of several aqueous extracts from wild (1a, 2a, 3a, 1b, 2b, and 3b) and cultivated (CAN1 °F, 3A, 2B(II), and CAN2 °F) P. nebrodensis basidiomes in human keratinocytes (HaCaT cells). Extracts were characterized through DPPH radical scavenging assay, MTT viability assay, and intracellular ROS and mitochondrial SOX quantification by DCFH-DA and MitoSOX Red fluorescence analyses. The methodology specifically included two approaches in keratinocytes: co-treatment of extracts and H₂O₂ to investigate direct scavenger activity, and pre-treatment to assess the preventive activity on oxidative stress modulation. This analysis demonstrated that selected extracts (1b and CAN2 °F) exert a dual action, combining anti-intracellular ROS and anti-mitochondrial SOX preventive effect with a direct free radical scavenging activity in human keratinocytes. In particular, CAN2 °F exerts its activity predominantly through prevention (modulation of cellular defenses), while 1b primarily functions as a direct intracellular ROS and mitochondrial SOX scavenger. Notably, glucan quantification revealed a correlation between β-glucan content and the overall antioxidant activity. These findings provide the first evidence of P. nebrodensis’s anti-ROS and anti-SOX efficacy in human keratinocytes, highlighting its potential as a source of natural bioactives for cosmeceutical and dermatological applications.