Karyorrhexis (from Greek κάρυον karyon, "kernel, seed, nucleus," and ῥῆξις rhexis, "bursting") is the destructive fragmentation of the cell nucleus that occurs in a dying cell. It is characterized by the breakdown of the nuclear envelope and the dispersal of condensed chromatin into the cytoplasm. The process is usually preceded by pyknosis (irreversible chromatin condensation) and followed by karyolysis (enzymatic dissolution of chromatin). It may occur during programmed cell death (apoptosis), cellular senescence, or necrosis. ^{[citation needed]}

In apoptosis, karyorrhexis is mediated by Ca²⁺- and Mg²⁺-dependent endonucleases, ensuring that nuclear fragments are packaged into apoptotic bodies and removed by phagocytosis. In necrosis, by contrast, nuclear fragmentation occurs in a less orderly fashion, leaving behind cellular debris that can contribute to tissue damage and inflammation.

In the intrinsic pathway of apoptosis, cellular stressors such as oxidative stress activate pro-apoptotic members of the Bcl-2 protein family, leading to permeabilization of the mitochondrial outer membrane. This releases cytochrome c into the cytoplasm, triggering a signaling cascade that culminates in the activation of multiple caspase enzymes. Among these, caspase-6 cleaves nuclear lamina proteins such as lamin A/C, structural components that maintain the integrity of the nuclear envelope. Their cleavage facilitates the controlled dissolution of the nuclear envelope during apoptosis.

During karyorrhexis in apoptosis, nuclear DNA is cleaved in an orderly fashion by endonucleases such as caspase-activated DNase, producing discrete nucleosomal fragments. This organization is possible because DNA has already undergone condensation during pyknosis, being tightly wrapped around histone proteins in repeating units of ≈180 bp. Activated endonucleases cleave the linker DNA between histones, generating short, regularly sized fragments that correspond to nucleosomal units. These DNA fragments can be visualized by gel electrophoresis, where they produce a characteristic “ladder” pattern, a hallmark used to distinguish apoptosis from other forms of cell death.

In apoptosis, karyorrhexis is a controlled process in which caspases degrade lamin proteins, leading to the orderly breakdown of the nuclear envelope. In less regulated forms of cell death, such as necrosis, nuclear degradation occurs through different mechanisms. Necrotic cells are characterized by rupture of the plasma membrane, lack of caspase activation, and the induction of an inflammatory response. Because necrosis is caspase-independent, the nucleus may remain intact during early stages before rupturing as a result of osmotic stress and membrane damage.

A specialized form of necrosis, necroptosis, involves a more regulated pathway but still results in plasma membrane rupture. Here, nuclear destabilization is mediated by the protease calpain, which cleaves lamins and promotes nuclear envelope breakdown.

Unlike karyorrhexis in apoptosis, which generates apoptotic bodies subsequently removed by phagocytosis, karyorrhexis in necroptosis leads to the uncontrolled release of intracellular contents into the extracellular space, where they are cleared primarily through pinocytosis.

Apoptosis, and the associated nuclear degradation through karyorrhexis, can be triggered by a variety of physiological and pathological stimuli. DNA damage, oxidative stress, hypoxia, and infections activate signaling cascades that converge on the intrinsic apoptotic pathway. This pathway may also be induced by external factors such as ethanol, which promotes activation of apoptosis-related proteins including BAX and caspases.