Therapeutic modulation of unfolded protein response by biochemic tissue salts in alcohol- and acetaminophen-induced liver cirrhosis

• Liver cirrhosis was induced by chronic alcoholism and acetaminophen. • Natrum sulphuricum and Natrum phosphoricum effectively treated liver cirrhosis towards normal. • Natrum sulphuricum and Natrum phosphoricum altered the nature of protein misfolding and genes of UPR pathway. Alcohol-associated liver disease (ALD) is a major global public health problem with chronic alcohol use responsible for a large proportion of alcohol-attributed fatalities. The combined exposure to acetaminophen raises the level of hepatotoxicity. The unfolded protein response (UPR) is one of the key cellular processes stimulated following liver injury but whose regulation under dual alcohol and acetaminophen treatment is ill defined. While Natrum sulphuricum (NS) and Natrum phosphoricum (NP) are Western biochemic homeopathic tissue salts, mineral salts and allied compounds have been traditionally used in Traditional Chinese Medicine (TCM) for the upkeep of liver and digestive functions. The present study was aimed at ascertaining hepatoprotective action of NS and NP through modulation of UPR signaling in chemically induced liver cirrhosis rat model. control, alcohol control, liver cirrhosis, LC+NS, and LC+NP. Liver cirrhosis was induced by chronic oral treatment with alcohol and acetaminophen. NS and NP were given orally for four weeks following induction. Liver tissues were taken for molecular analysis, and expression of a few of the major UPR-related genes and proteins were quantified by quantitative RT-PCR and Western blotting. Both acetaminophen and alcohol coexposures significantly dysregulated UPR markers, suggesting endoplasmic reticulum stress and altered proteostasis. NP and NS treatment restored levels of key UPR components, suggesting therapeutic protein-folding mechanism modulation. NS and NP showed hepatoprotective action through UPR signaling modulation and reduction of protein-misfolding stress in chemically induced liver cirrhosis. These results are preliminary scientific basis to explore mineral-based compounds in new and traditional medicine settings, including their theoretical significance to TCM approaches to the prevention of liver disease.