# Proline Metabolism in Cancer: Emerging Roles in Redox Homeostasis and Therapeutic Opportunities

## TL;DR

This paper reviews how proline metabolism supports cancer cell energy needs and explores its potential as a new target for cancer treatments.

## Contribution

The paper highlights the emerging role of proline metabolism in cancer redox balance and therapeutic opportunities.

## Key findings

- Proline metabolism is rewired in cancer to support energy production and redox homeostasis.
- Proline metabolism varies across cancer subtypes, offering context-dependent therapeutic potential.
- Targeting proline metabolism could lead to novel, precise cancer treatments.

## Abstract

Cancer can cause uncontrolled cell growth and spread to distant locations within the body, which requires large amounts of energy. To acquire the needed energy, cancer cells alter signaling pathways and harvest nutrients from the surrounding environment. One pathway that has emerged to be rewired is proline metabolism, in which the amino acid proline is utilized for protein synthesis and is catabolized in the mitochondrion, driving ATP production and redox homeostasis involving the NAD+/NADH balance and reactive oxygen species. Cancer cells increase the efficiency of proline-dependent energy production by changing signaling pathways, coupling metabolic and redox cycles, and balancing collagen production and degradation. Because of the multiple roles of proline in cancer progression, targeting proline metabolism has gained strong interest as a novel approach for inhibiting cancer progression. This review summarizes the various aspects of proline metabolism in different types of cancer and discusses strategies for developing new cancer therapeutics.

Cancer is a complex disease characterized by uncontrolled proliferation and progression toward metastasis. The activation and maintenance of these processes demand increased energy production. Traditional cancer therapies often target broad energy-generating mechanisms to inhibit cancer growth. However, the field of oncology is increasingly shifting toward more potent, precise, and personalized treatment strategies. This shift has fueled interest in novel cancer metabolic pathway targets. This review focuses on proline metabolism, an amino acid pathway that has been observed to be altered across various cancer subtypes. Proline has emerged as one of the most consistently deregulated non-essential amino acids in cancer biology. Proline metabolism is intimately linked to mitochondria function and energy regulation through mechanisms such as reactive oxygen species, ATP production, and interactions with the tumor microenvironment. Due to its dichotomous nature, proline metabolism functions are highly context dependent, varying across cancer subtypes. While this provides a potential novel therapeutic target, it also presents unique challenges and knowledge gaps.