Graphical Abstract Highlights d Mitochondria play a pivotal role in cysteine-deprivationinduced (CDI) ferroptosis d Mitochondrial membrane potential hyperpolarization is associated with CDI ferroptosis d TCA cycle, electron transport chain, and glutaminolysis function in CDI ferroptosis d Mutation of tumor suppressor fumarate hydratase confers resistance to CDI ferroptosis

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing1–3. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence4,5, a form of terminal cell cycle arrest associated with pro-inflammatory responses6. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA sensing cGAS-STING pathway, leading to both short-term inflammation to restrain activated oncogene and chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype (SASP) in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents, and is associated with human diseases1–3. While extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known regarding the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery4–6, is present in the nucleus and directly interacts with the nuclear lamina protein Lamin B1, and binds to lamin-associated domains (LADs) on chromatin. This LC3-Lamin B1 interaction does not downregulate Lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated Ras. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers Lamin B1 to the lysosome. Inhibiting autophagy or the LC3-Lamin B1 interaction prevents activated Ras-induced Lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests this new function of autophagy as a guarding mechanism protecting cells from tumorigenesis.

Cellular metabolism is at the foundation of all biological activities. The catabolic processes that support cellular bioenergetics and survival have been well studied. By contrast, how cells alter their metabolism to support anabolic biomass accumulation is less well understood. During the commitment to cell proliferation, extensive metabolic rewiring must occur in order for cells to acquire sufficient nutrients such as glucose, amino acids, lipids and nucleotides that are necessary to support cell growth, and to deal with the redox challenges that arise from the increased metabolic activity associated with anabolic processes. Defining the mechanisms of this metabolic adaptation for cell growth and proliferation is now a major focus of research. Understanding the principles that guide anabolic metabolism may ultimately enhance ways to treat diseases that involve deregulated cell growth and proliferation, such as cancer. eTOCCell proliferation is associated with substantial rewiring of metabolism to support extensive need for macromolecule biosynthesis. Better understanding of how cells acquire and utilize nutrients for biosynthetic pathways and how they cope with metabolic challenges linked to high rates of proliferation will lead to improved cancer treatments.

SUMMARYTP53 is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumor suppressive function and lead to “gain-of-function” (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases KMT2A (MLL1) and KMT2D (MLL2), and acetyltransferase KAT6A (MOZ or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumors, but not in p53 wildtype or p53 null tumors. Cancer cell proliferation is dramatically lowered by genetic knockdown of MLL1, or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumors with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.