# Lead induces cell-autonomous proliferation and metabolic reprogramming of hepatocytes

## TL;DR

Lead nitrate causes non-cancerous liver cells to behave like cancer cells by changing their metabolism and increasing their growth.

## Contribution

This study shows that lead nitrate directly reprograms liver cell metabolism and promotes growth without needing other liver cells.

## Key findings

- Lead nitrate induces cancer-like metabolic changes in non-tumorigenic hepatocytes.
- NRF2 activation is essential for lead-induced metabolic reprogramming and cell proliferation.
- Triiodothyronine does not cause metabolic reprogramming despite promoting liver cell growth.

## Abstract

Reprogramming of energy metabolism is widely recognized as a hallmark of cancer cells. However, recent evidence indicates that metabolic reprogramming also occurs in vivo in differentiated rat hepatocytes following administration of the primary mitogen lead nitrate (LN). It remains unclear whether this phenomenon results from a direct action of LN on hepatocytes or is mediated by non-parenchymal liver cells. In our study, we investigated the cell-autonomous effects of LN using immortalized non-tumorigenic rat (RNT) and human (THLE-2) hepatocytes. LN treatment induced cancer-like metabolic features in non-tumorigenic hepatocytes, including increased glycolysis, activation of both oxidative and non-oxidative pentose phosphate pathways (PPP), and reduced oxidative phosphorylation (OXPHOS). Additionally, LN increased several targets of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2), a key regulator of cellular defense against stress. We found that activation of the Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 pathway was associated with increased hepatocyte proliferation. Importantly, silencing NRF2 completely abolished the LN-induced metabolic reprogramming. In contrast, triiodothyronine (T3), a liver mitogen that does not activate NRF2, failed to trigger metabolic reprogramming. Overall, our findings demonstrate that LN directly drives both proliferation and metabolic reprogramming in hepatocytes, independently of microenvironmental or immune signals. NRF2 plays a central role as a key driver of these cancer-like metabolic shifts, even in non-tumorigenic cells.