Naringenin reduces oxidative stress and necroptosis, apoptosis, and pyroptosis in random-pattern skin flaps by enhancing autophagy

Random skin flap grafting is one of the most commonly used techniques in plastic and orthopedic surgery. However, necrosis resulting from ischemia and ischemia-reperfusion injury in the distal part of the flap can severely limit the clinical application of the flap. Studies have revealed that naringenin reduces pyroptosis, apoptosis, and necroptosis, inhibits oxidative stress, and promotes autophagy. In this study, the effects of Naringenin on flap viability and its underlying mechanism were evaluated. Mice with random skin flaps were randomly allocated to control, Naringenin, and Naringenin + 3-methyladenine groups. On postoperative day 7, flap tissues were collected to estimate angiogenesis, necroptosis, apoptosis, pyroptosis, oxidative stress, and autophagy via hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The results revealed that naringenin promoted the viability of the random flaps as well as angiogenesis, while inhibiting oxidative stress and decreasing pyroptosis, apoptosis, and necroptosis. These effects were reversed by the autophagy inhibitor 3-methyladenine. The findings indicated that naringenin treatment could promote flap survival by inhibiting pyroptosis, apoptosis, necroptosis, and alleviating oxidative stress, caused by the activation of autophagy.