Our manuscript entitled "Extracellular NAD+ Response to Post-Hepatectomy Liver Failure: Bridging Preclinical and Clinical Findings" has been accepted for publication in Communications Biology. Authors are Can Kamali, Philipp Brunnbauer, Kaan Kamali, Al-Hussein Saqr, Alexander Arnold, Gulcin Harman Kamali, Julia Babigian, Eriselda Keshi, Raphael Mohr, Matthäus Felsenstein, Simon Moosburner, Karl Hillebrandt, Jasmin Bartels, Igor Sauer, Frank Tacke, Moritz Schmelzle, Johann Pratschke, and Felix Krenzien.

Liver fibrosis progressing to cirrhosis is a major risk factor for liver cancer, impacting surgical treatment and survival. Our study investigates extracellular Nicotinamide adenine dinucleotide (eNAD+) in liver fibrosis, analyzing patients undergoing surgery and exploring NAD+'s therapeutic potential in a mouse model of extended liver resection and in vitro using 3D hepatocyte spheroids.

eNAD+ correlated with aspartate transaminase (AST) and bilirubin after liver resection (AST: r = 0.2828, p = 0.0087; Bilirubin: r = 0.2584, p = 0.0176). Post-hepatectomy liver failure (PHLF) was associated with higher eNAD+ peaks (n = 10; p = 0.0063). Postoperative eNAD+ levels decreased significantly (p < 0.05), but in advanced liver fibrosis or cirrhosis, this decline diminished or increased. NAD+ biosynthesis enzymes, NAMPT and NMNAT3, were significantly upregulated in higher fibrosis stages (p < 0.0001). NAD+ administration in 3D hepatocyte spheroids rescued hepatocytes from TNFα-induced cell death and improved viability (p < 0.0001). In mice, NAD+ treatment significantly improved survival (p = 0.0155) and liver regeneration (p = 0.0186) after extended liver resection.

eNAD+ is upregulated in PHLF, and NAD+ biosynthesis enzymes show higher expression in liver fibrosis. eNAD+ administration improved survival and hepatocyte viability, offering a potential target for future therapies.