Researchers at Osaka Metropolitan University have identified two proteins that drive liver scarring and demonstrated they can be blocked—a breakthrough that could offer hope to millions living with liver fibrosis, a progressive condition that currently has no approved therapy despite decades of research.
The liver is a "silent organ," capable of enduring significant damage without obvious warning signs. But when injury persists—from alcohol, poor diet, or chronic hepatitis virus infection—the organ hardens and scars in a process called fibrosis. Left untreated, this scarring advances to cirrhosis and liver cancer, one of the world's leading causes of cancer death. What makes fibrosis particularly vexing is its unpredictability: some patients, like those who successfully clear hepatitis C, spontaneously heal and their scarring retreats. Others continue to deteriorate despite similar circumstances. Understanding why the liver can regenerate in some cases but not others has remained largely unanswered for decades.
Associate Professor Le Thi Thanh Thuy and Professor Norifumi Kawada led a team that deployed a cutting-edge technique called single-cell fixed RNA profiling—applied to liver fibrosis research for the first time—to analyze the gene activity of approximately 38,000 individual liver cells from healthy, fibrotic, and recovering mouse livers. The method produced a precise cellular "atlas," a detailed map of how every major liver cell type changes as fibrosis progresses and, crucially, as it heals. Their findings, published in JHEP Reports, revealed two molecular targets with clear therapeutic potential.
The first protein is semaphorin-4D (SEMA4D). During fibrosis, immune cells called monocyte-derived macrophages release SEMA4D, which acts as a "distress signal" to hepatic stellate cells—the primary scar-producing cells in the liver. When researchers treated fibrotic mice with VX15/2503, a humanized antibody that blocks SEMA4D, fibrosis significantly decreased. Importantly, elevated SEMA4D was also found in human liver biopsies from patients with advanced fibrosis, and when patients cleared hepatitis C, their SEMA4D levels declined in correlation with reduced risk of liver cancer progression.
The second target is LIM and cysteine-rich domains 1 (LMCD1), a transcription factor operating inside stellate cells themselves. Rather than responding to external signals, LMCD1 functions as an internal "master switch" that keeps stellate cells locked in an active, scar-producing state. The research showed LMCD1 is highly expressed during fibrosis but suppressed during healing. Silencing LMCD1 in the laboratory reduced fibrotic protein production, while forcing its overexpression drove scarring through the AKT/mTOR signaling pathway. Like SEMA4D, LMCD1 levels in human samples correlated with fibrosis severity across both fatty liver disease and hepatitis C patient populations.
The convergence of these findings in both mice and human tissue suggests these two molecules are driving fibrosis in real patients and, most importantly, can be blocked. The team's work indicates that targeting both proteins simultaneously through combination therapy could potentially halt disease progression—offering a pathway forward for the millions who currently have no effective treatment options.