Iron chelation as a new therapeutic approach to prevent senescence and liver fibrosis progression

Chronic liver injury of various etiologies leads to fibrosis, which may progress toward cirrhosis and carcinogenesis [1]. The process occurs through a combination of different events: hepatocyte damage [2], inflammation [3], and activation of the hepatic stellate cells (HSC) into myofibroblasts, the main producers of extracellular matrix (ECM) proteins [4, 5]. Accumulating data derived from clinical and experimental studies have indicated that cellular senescence plays a relevant role in the occurrence and development of liver disease [6]. However, depending on the cells that become senescent, the results may differ. On one side, senescent hepatocytes accumulate in chronic liver diseases and create a pro-inflammatory environment as part of the senescence-associated secretory phenotype (SASP), which activates HSCs [7, 8] and impairs liver regeneration [9, 10], contributing to fibrosis progression. On the other side, senescence of myofibroblasts decreases the secretion of ECM, increases the expression of ECM-degrading enzymes, enhances immune surveillance, and, consequently, reduces liver fibrosis in mice [11]. Indeed, the design of specific senolytic agents that would act preferentially on hepatocytes but not on HSCs might represent a new therapeutic tool in liver fibrosis.

Different studies have shown that iron overload is associated with liver pathologies, triggering oxidative stress and mitochondrial dysfunction. The clearest example is the accumulation of iron in hepatocytes in hereditary hemochromatosis [12], but iron overload may also be a risk factor during the development and progression of metabolic diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) [13], or in alcohol-associated liver disease (ALD) [14]. Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C [15]. Mice lacking hepcidin, a central regulator of iron homeostasis produced by hepatocytes, develop chronic liver injury and liver fibrosis [16]. Moreover, it has been proposed that high levels of TGF-β mediate BMP2 reduction, which contributes to hepcidin downregulation in patients with liver fibrosis [17]. Despite this evidence, additional work is necessary to better understand whether iron overload is a general characteristic of chronic liver diseases and which are the underlying mechanisms by which excess iron can facilitate fibrotic responses [18].

We have recently proposed that iron accumulation could play a role in senescence and fibrosis in the kidney and lung [19]. In the case of the liver, it has been proposed that iron loading of hepatocytes in hereditary hemochromatosis leads to impaired replication and senescence, correlating with hepatic fibrosis [20]. However, compelling evidence of a correlation between iron accumulation and senescence in other liver pathologies is currently lacking.

The aim of this study was to delve into the role of iron and senescence in an experimental model of chronic liver injury and analyze whether an iron chelator would prevent the progression of liver fibrosis by decreasing hepatocyte senescence.