A study recently published in Chemico-Biological Interactions explores the biochemical mechanisms of liver damage in patients receiving obeticholic acid (OCA), a drug that was previously prescribed to patients with primary biliary cholangitis (PBC) until its withdrawal earlier this month.
OCA (marketed as Ocaliva) was approved by the U.S. Food and Drug Administration (FDA) in 2016 for individuals with PBC who did not respond to ursodeoxycholic acid. However, the drug company withdrew Ocaliva from the U.S. market in September 2025 after an FDA request citing clinical trials in which patients experienced serious liver injury while on the drug.
“In clinical practice, the main reason for the occurrence of OCA-induced liver injury reported by the FDA Adverse Event Reporting System is the patient’s own liver dysfunction,” the study’s authors wrote.
In their study, the researchers evaluated the effects of OCA in mice with liver disease. Findings revealed that OCA administration led to increased levels of high-mobility group box 1 (HMGB1), a protein that is released in response to tissue damage and necrosis. HMGB1 is implicated in a number of acute and chronic liver diseases.
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Mechanistic analysis showed that OCA prevented liver cells from recycling damaged or old cell components, leading to the release of HMGB1. In particular, OCA damaged the cell organelles required for waste disposal, causing them to leak their contents into the rest of the cell.
When the researchers gave the OCA-treated mice ethyl pyruvate, a chemical that blocks HMGB1, they saw that tissue death and inflammation were significantly reduced.
The authors recommend that future research be conducted to determine whether introducing a drug to block HMGB1 can improve the safety of OCA in patients with PBC. If effective, this strategy could potentially result in the reinstatement of OCA on the market. However, it would take many studies — and many years — for such a combination therapy to be approved.
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