Hepatic ischemia reperfusion injury (HIRI) is a common and inevitable pathological consequence in clinical liver surgeries. Reduced hepatic blood flow during the ischemia phase leads to decreased tissue oxygenation and nutrition, resulting in depletion of adenosine triphosphate (ATP). Resident liver cells are forced to shift to anaerobic metabolism, eventually leading to cell death [1]. Ruptured cell membrane causes leakage of damage-associated molecular patterns (DAMPs), which initiate the inflammatory signaling cascades [2]. In the subsequent reperfusion phase, DAMPs are flushed into the circulation, triggering a more severe inflammatory response. Therefore, current therapeutic strategies for HIRI are mainly focused on alleviating inflammatory response [3].

Macrophages are abundant in healthy rodent livers, with 20–40 macrophages per 100 hepatocytes [4]. In addition to sensing DAMPs to prime inflammatory response and recruit circulating immune cells to injured tissue, macrophages contribute to inflammation resolution and tissue repair in HIRI [5]. The uptake of apoptotic neutrophils promotes the polarization of macrophages towards the M2 phenotype, thus facilitating the resolution of inflammation [6]. The multistep process by which phagocytes clear apoptotic cells is termed as efferocytosis [7]. Defective efferocytosis has been widely proved to be implicated in inflammatory disease [8].

Calorie restriction (CR) is considered to be the most robust intervention to extend life span and improve chronic health problems [9]. Caloric restriction mimetics (CRMs) have recently gained attention for simulating the effects of CR and increasing the convenience of CR applications [10]. Among multitudinous CRMs, resveratrol (RSV), a natural polyphenol synthesized exclusively by plants, has been reported to modulate macrophages recruitment [11]. While RSV is believed to induce M2 polarization of macrophages, its ability to promote efferocytosis has not been verified. Here we assumed that CR mimetic, RSV, could enhance M2 polarization and promote the efferocytosis of macrophages, thereby facilitating the clearance of apoptotic neutrophils and attenuating HIRI. This study disclosures a new potential mechanism by which RSV alleviates HIRI and provides a theoretical support for the implementation of RSV in clinical applications.