Hepatic
ischemia-reperfusion injury (HIRI), a common two-phase intersocietal reaction in liver surgery, typically leading to sustained
liver dysfunction. During this process, liver sinusoidal endothelial cells (LSECs) are vulnerable to damage and exert senescence-associated secretory phenotype (SASP). However, how these SASP-LSECs secreted damage-associated molecular patterns (DAMPs) to impact the whole HIRI microenvironment and whether it can be reversed by
therapeutics remains unknown. Here, we found that either HIRI surgery or
hypoxia and reoxygenation (HR) stimulation forced LSECs into SASP and expressed HMGB1-dominated DAMPs, which were dramatically improved by
acteoside (ACT). Additionally, hypoxic hepatocytes released excessive
HMGB1 to LSECs and synergistically aggravated their SASP state. Mechanistically,
HMGB1 bound with TLR3/TLR4 on LSECs, promoted the nuclear translocation of IRF1 and subsequent transcription of cxcl1 and
Hmgb1, leading to the chemotaxis of neutrophils and accelerating immune damage in a vicious circle. Notably, ACT or
HMGB1 siRNA effectively disrupted
HMGB1-TLR3/4 interaction, leading to IRF1 inhibition and repairing LSEC functions, which was largely reversed by
HMGB1 stimulation and IRF1-overexpressed
liposomes with LSECs-targeted
hyaluronic acid-derivative conjugated in mice. Collectively, ACT reversed the senescent fate of LSECs and restored sinusoidal networks by targeting
HMGB1-TLR3/4-IRF1 signaling, thus providing protection against HIRI and offering the potential for new
therapeutics development.