In short, it is to infer that it is well documented that high fat diet induces Peroxisomal damage by the production of increased FAO, oxidative stress, accumulation of reactive oxygen species, and lastly but not the least the effects of inflammation and fibrosis. All these contribute to initiate malignant transformation of hepatocytes by pro-inflammatory signaling pathway and DNA damage.

Yes, your hypothesis is plausible, and it aligns with what is increasingly understood about peroxisome biology, oxidative stress, and liver tumorigenesis. Let me break it down step by step:

---

1. High-fat diet, fatty acid overload, and FAO

A high-fat diet (HFD) increases lipid influx into hepatocytes.

Both mitochondria and peroxisomes handle fatty acid β-oxidation.

Peroxisomes preferentially metabolize very-long-chain and branched-chain fatty acids, producing H₂O₂ as a by-product through acyl-CoA oxidases.

---

2. ROS accumulation and peroxisomal vulnerability

Unlike mitochondria, peroxisomes lack a respiratory chain, but their β-oxidation generates large amounts of H₂O₂.

Peroxisomes normally counter this via catalase and other antioxidant enzymes.

Chronic lipid overload (as in HFD) can overwhelm this defense, leading to peroxisomal damage, membrane permeabilization, and ROS leakage.

Damaged peroxisomes also lose the ability to regulate ROS detoxification, exacerbating oxidative stress.

---

3. Peroxisome–mitochondria crosstalk

Peroxisomes and mitochondria are metabolically and physically connected.

Dysfunctional peroxisomes can worsen mitochondrial ROS generation, impair lipid handling, and disturb redox balance.

This amplifies oxidative stress, DNA damage, and inflammation in hepatocytes.

---

4. Progression toward HCC

Sustained oxidative stress damages DNA, proteins, and lipids in hepatocytes.

This leads to mutations, genomic instability, and chronic inflammation (hallmarks of hepatocarcinogenesis).

In NAFLD/NASH–HCC models, impaired peroxisomal function is increasingly recognized as a driver of disease progression.

Animal studies show that peroxisome dysfunction (e.g., catalase deficiency or peroxisome loss) worsens fatty liver, fibrosis, and tumorigenesis.

---

✅ Conclusion:

Your hypothesis is scientifically reasonable: peroxisomal damage induced by an HFD could reduce peroxisomes’ capacity to detoxify ROS, leading to higher oxidative stress, which contributes to hepatocellular carcinoma onset. While mitochondrial dysfunction is often emphasized, peroxisomal damage is now emerging as a key player in HFD-driven liver cancer.